(UroToday.com) The 2023 American Society of Clinical Oncology (ASCO) annual meeting included a testicular cancer session, featuring a presentation by Dr. Lucia Nappi discussing long-term follow-up analysis of plasma miR371 expression to detect early relapse in patients with clinical stage I testicular germ cell tumors on surveillance. Micro-RNAs are small non-coding RNA regulating oncogenes and oncosuppressor transcription. Two micro-RNA clusters are overexpressed in germ cell tumors, both seminoma and non-seminoma but not in teratoma:
miR371 is considered pathognomonic for viable germ cell malignancy, given that it is only expressed in pregnancy and germ cell malignancy, with serum/plasma levels correlated with clinical stage. Additionally, there is a rapid decrease and disappearance after successful treatment. Unfortunately, CT scan and serum tumor markers have limited accuracy in detecting early stage germ cell tumors.
Clinical Stage I (CSI) is the most common presentation of germ cell testicular tumors and patients are usually managed with active surveillance, in the absence of reliable biomarkers of relapse. Circulating plasma miR371 has demonstrated high sensitivity and specificity in advanced non teratoma germ cell tumors. However, its operating characteristics and power to detect early relapse are still undefined.
CSI germ cell tumor patients enrolled in the British Columbia provincial biobank with available plasma samples after radical orchiectomy were included in this study:
Plasma miR371 was qualitatively assessed by RT-PCR. Sensitivity, specificity, negative and positive predictive values (NPV, PPV) and AUC in predicting tumor recurrence were evaluated in the post-orchiectomy blood samples and/or during the follow-up prior to or at the time of the clinically evident relapse. Additionally, relapse free survival was correlated to post-orchiectomy miR371 status. The primary objective of the study was to establish the accuracy of miR371 in detecting active germ cell malignancy in early stage germ cell tumor:
- Prior to clinically evidence relapse (post-orchiectomy to detect minimal residual disease)
- During follow-up at the time of early stage (IIA/early IIB) relapse
There were 298 patients queried, ultimately leading to 101 patients analyzed (36 nonseminoma, 65 seminoma):
Ultimately, 35 (34.6%) patients experienced a disease relapse with a median follow-up of 41 months:
Longitudinal evaluation showed that miR371 positivity preceded clinical evident disease by a median of 3 months (range: 1-12 months):
miR371 was positive in 22/35 of the relapsed patients. In the entire cohort, the specificity and PPV were 100% (both 95% CI 94.5 - 100), sensitivity 62.8% (95% CI 44.9 - 78.5), NPV 83.5% (95% CI 76.7 - 88.6) and AUC 0.81 (95% CI 0.71 - 0.91). No false positive results were observed. When stratified by seminoma (AUC 0.78) and nonseminoma (AUC 0.83) the accuracy of the cohort is as follows:
The relapse free survival of the patients with positive post-orchiectomy miR371 was significantly shorter (median: 3.5 months vs. not reached; p<0.0001) compared to the patients with a negative post-orchiectomy miR371 (HR 16.95, 95% CI 2.11 - 135.7):
In the post-orchiectomy cohort, 15/68 (22%) experienced tumor relapse, with no false positives being observed. Over a median follow-up of 32 months, the specificity and PPV were 100% (both 95% CI 93.2 - 100), sensitivity 53.3% (95% CI 26.5 - 78.3), NPV 88.3% (95% CI 79.9 - 95.7) and AUC 0.76 (95% CI 0.60 - 0.93):
When stratified by histology post-orchiectomy, the AUC for seminoma patients was 0.72 (95% CI 0.49 – 0.94) and for nonseminoma was 0.83 (95% CI 0.59-1.0).
So, is miR371 ready to be integrated into our clinical practice as the ideal biomarker? Dr. Nappi notes that the SWOG S1823 “A Prospective Observational Cohort study to Assess miRNA 371 for Outcome Prediction in Patients with Newly Diagnosed Germ Cell Tumors Trial” is currently assessing clinical utility and clinical validity. S1823 was activated in the US on June 1, 2020, with the first patient being consented on July 27, 2020. In Canada, the study was opened in December 2020, and currently (as of May 22, 2023) 732 of 956 patients have been enrolled, with the high risk group already fully accrued.
Dr. Nappi concluded her presentation discussing long-term follow-up analysis of plasma miR371 expression to detect early relapse in patients with CSI testicular germ cell tumors on surveillance with the following take-home points:
- miR371 has high specificity, PPV and NPV in detecting germ cell tumor at an early stage with a follow-up longer than the expected median time of relapse
- Sensitivity appears to be more dependent on tumor burden and histology than specificity and PPV
- In the baseline post-orchiectomy false negative patients, miR371 became detectable during the follow-up prior to / or at the time of relapse with a median time of relapse anticipation of 3 months
- More sensitive methodologies to detect extremely low circulating miR371 copies are under development and could improve the sensitivity of the test also in patients with subclinical tumor
- The S1823 clinical trial will establish the operating characteristics of miR371 in detecting minimal residual disease in CSI patients and will define the timing of miR371 positivity switch during the follow-up of these patients to detect tumor relapse
Presented by: Lucia Nappi, MD, PhD, Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023.