miR-371a-3p Predicting Viable Tumor in Patients Undergoing Retroperitoneal Lymph Node Dissection for Metastatic Testicular Cancer: The SWENOTECA-MIR Study

Abstract

Purpose: The SWENOTECA-MIR prospective multicenter study aims to assess the clinical value of miR-371a-3p as a novel marker in metastatic germ cell tumor patients undergoing retroperitoneal lymph node dissection (RPLND), to predict the presence of viable residual tumor.<p>

<p>Materials and Methods: A total of 114 patients (86 nonseminomas, 28 seminomas) who underwent surgery for presumed metastatic disease pre chemotherapy (primary RPLND) and post chemotherapy RPLND were included. The expression of miR-371a-3p was evaluated using reverse transcription–digital droplet polymerase chain reaction before and after RPLND. Pre- and postoperative miR-371a-3p levels were statistically compared, and optimism-corrected performance calculations compared with conventional serum tumor markers. Associations were evaluated by logistic regression. Patients who underwent primary RPLND were categorized into seminoma and nonseminoma groups.<p>

<p>Results: - Among the seminoma patients (n = 24) undergoing primary RPLND, all had normal conventional markers. Six patients received adjuvant treatment before surgery. miR-371a-3p exhibited a sensitivity of 74%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 21% for viable tumor. The levels of miR-371a-3p significantly decreased after surgery. In the nonseminoma group (n = 18) treated with primary RPLND, 22% had elevated conventional markers and 3 had received prior adjuvant treatment. miR-371a-3p showed a sensitivity of 34%, specificity of 88%, positive predictive value of 67%, and negative predictive value of 62% for the primary nonseminoma patients. No association was observed between stage or prior adjuvant treatment and the outcome of the miR test. In the postchemotherapy group (n = 72), the miR-371a-3p sensitivity was 9%, reducing to 0 when excluding patients with seminoma (n = 4). Teratomas and benign histology were essentially negative.<p>

<p>Conclusions: Our study highlights miR-371a-3p as a fairly sensitive and highly specific marker for prechemotherapy seminomas, outperforming conventional markers. However, in prechemotherapy nonseminomas as well as in postchemotherapy patients, we observed low sensitivity and no significant differences in miR-371a-3p levels before and after surgery, suggesting limited utility for miR-371a-3p in this context.<p>

<p>Testicular germ cell tumor (TGCT) is the most common cancer in young males, with rising incidence.1 Although treatment for metastatic TGCT is highly effective, the chemotherapy regimens used are associated with significant long-term side effects, including cardiovascular disease and secondary malignancies.2 Survivors may also experience excess mortality due to prior therapy.3<p>

<p>Staging and monitoring of TGCTs involve repeated CT and MRI, and measuring serum protein biomarkers beta human chorionic gonadotropin (β-hCG), alpha fetoprotein (AFP), and lactate dehydrogenase. However, the markers lack sensitivity and specificity, with 40% of all TGCTs being marker negative, especially seminomas and teratomas.4<p>

<p>Chemotherapy typically includes bleomycin, etoposide, and cisplatin (BEP) courses varying by clinical stage (CS) and risk group. Adjuvant treatment by one course of carboplatin or BEP is offered to selected CS I patients, according to the SWENOTECA protocol. BEP was administered as adjuvant treatment to seminoma patients within the randomized ABC-study.5 Surgery is indicated for nonseminoma patients with a visible residual tumor ≥ 10 mm in the retroperitoneum after first-line chemotherapy,5 while for seminoma patients with small retroperitoneal metastases, surgery is being evaluated as a primary treatment in prospective clinical trials.6-8 Retroperitoneal lymph node dissection (RPLND) is a complex surgical procedure, associated with perioperative morbidity and risk of long-term sequelae, including loss of antegrade ejaculation. In previous studies, 44% to 72% of RPLND patients harbored only necrosis or fibrosis in residual masses.9-11 Reliable diagnostic tools are needed to distinguish patients requiring RPLND from those who can be spared.<p>

<p>In 2011, the microRNA clusters miR-302/367 and miR-371 to 373 were identified as potential novel markers for TGCTs.12 Subsequent research revealed miR-371a-3p as the most promising micro-RNA marker, as it has been found to be present in nearly all cases of TGCTs other than teratoma.13-16 Dieckmann et al demonstrated that miR-371a-3p expressed sensitivity and specificity over 90% in TGCTs at various CSs.14 Further studies reported similar results for miR-371a-3p in postchemotherapy patients with retroperitoneal residual masses or relapse.17,18 Teratomas have consistently shown negative results in miR-371a-3p measurements across various studies.19<p>

<p>To determine the clinical value of the lead candidate miR-371a-3p as a tumor marker, large prospective clinical trials are required. The first part of the SWENOTECA-MIR study on miR-371a-3p in 180 orchiectomy patients showed better performance than conventional markers, with an overall sensitivity of 89%.20 This study aims to assess miR-371a-3p expression before and after RPLND in TGCT patients, to evaluate its accuracy and potential as a predictor of viable disease, and to see whether cytoreductive surgery affects its values.