SUO 2020: Clinical Application for Novel Biomarkers in Testis Cancer

• AFP is elevated in: hepatocellular carcinoma, liver disease, and in some familial conditions
• Beta-HCG is elevated in: bladder, renal, gastric, and lung cancers, as well as in men that use marijuana, in addition to cross-reactivity with LH
• LDH is elevated in any clinical setting with rapid cell turnover

The challenges are that there are several disease spaces in testis cancer that require different biomarkers and treatment considerations, specifically stage I disease, stage II seminoma, stage II non-seminoma, post-chemotherapy residual seminoma masses, detection of minimal residual disease after 1^st line therapy in intermediate/poor risk, detection of minimal residual disease after salvage chemotherapy or surgery, and late relapse.

Dr. Adra then went through several cases to illustrate the aforementioned clinical conundrums and how miRNA may be beneficial. The first patient was 40 years old with a suspicious left testicular mass who subsequently underwent a left radical orchiectomy, pathology demonstrating a 9 cm pure seminoma. His pre-orchiectomy tumor markers were negative and a CT scan showed a 13 x 15 mm periaortic lymph node inferior to the left renal artery. For this patient, is it stage I or stage IIA? At this point, he had a microRNA-371, which was negative, and subsequent biopsy demonstrated follicular lymphoma. The next case was that of a 39-year-old who underwent a right orchiectomy with pathology demonstrating a 4.5 cm seminoma. A CT scan 3 years later showed a 10 x 11 mm interaortocaval lymph node. Subsequently, he underwent a RPLND with 37/37 lymph nodes negative for malignancy; his preoperative microRNA-371 was negative. The final case was a 34-year-old that underwent a left orchiectomy, which showed 100% embryonal carcinoma; AFP and beta-HCG were normal pre- and post-orchiectomy, however, his CT showed enlarged retroperitoneal lymph nodes. One month later he underwent an RPLND that showed 9/37 lymph nodes positive for embryonal carcinoma and his post-RPLND microRNA-371 was negative. The question is, should he receive adjuvant therapy with a negative microRNA-371?

The following table shows differences in miRNA-371a-3p versus conventional tumor markers based on various parameters studied:

Dieckmann and colleagues assessed serum levels of microRNA-371 as a biomarker in a prospective multicenter study¹. There were 616 patients with testicular germ cell tumors and 258 male controls; for the primary diagnosis of germ cell tumor, the microRNA-371 test showed a sensitivity of 90.1%, a specificity of 94.0%, an area under the curve of 0.96, and a positive predictive value of 97.2%. AFP, beta-HCG, and LDH had sensitivities of less than 50% in seminoma and slightly higher sensitivities in non-seminomas. Additionally, microRNA-371 expression increased in patients with clinical stage II/III versus clinical stage I disease for both seminoma and NSGCT:

In a study of 111 men with a history of or newly diagnosed germ cell tumor, Nappi et al.² found that 35% of patients had clinically confirmed advanced germ cell tumor over the course of management. Among these patients, 96% had plasma miR371 expression (true positives) with no false positives. Furthermore, plasma miR371 expression in confirmed advanced germ cell malignancy had a specificity, sensitivity, positive predictive value, and negative predictive value of 100%, 96%, 100%, and 98%, respectively.

Dr. Adra notes that the ideal biomarker has the following characteristics:

• Highly sensitive (positive in the presence of disease)
• Highly specific (negative in the absence of disease)
• Non-invasive
• Routinely available
• Consistent (reproducible)
• Quick turnaround time
• Affordable

Indeed, there are remaining challenges for miRNA-371, including among patients with teratoma, germ cell neoplasia in situ, and improving standardization across labs.

Presented by: Nabil Adra, MD, Hematology Specialist, Assistant Professor of Clinical Medicine, Indiana University, Indianapolis, Indiana

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2020 Society of Urologic Oncology Annual Meeting – December 2-5, 2020 – Washington, DC

References:

1. Dieckmann KP, Radtke A, Geczi L, et al. Serum levels of MicroRNA-371a-3p (M371 Test) as a New Biomarker of Testicular Germ Cell Tumors: Results of a Prospective Multicentric Study. J Clin Oncol. 2019 Jun 1;37(16):1412-1423
2. Nappi L, Thi M, Lum A, et al. Developing a highly specific biomarker for germ cell malignancies: Plasma miR371 expression across the germ cell malignancy spectrum. J Clin Oncol. 2019 Nov 20;37(33):3090-3098.