2025-12-01
Will biomarkers save patients with refractory testicular germ cell tumors?
Oncology
By Lila Rouland | Published on December 1rst, 2025 | 3 min read
Metastatic testicular germ cell tumors (TGCTs) currently achieve high cure rates with cisplatin-based chemotherapy; however, 20–30% of patients relapse or exhibit resistance to first-line treatment. For those facing refractory or relapsed disease, the identification of prognostic and predictive biomarkers is becoming essential to optimize salvage strategies, including conventional chemotherapy or high-dose regimens followed by autologous stem-cell transplantation.
The clinical parameters currently used (histology, tumor markers, clinical features) remain insufficient for predicting treatment response. This 2023 review summarizes current knowledge on molecular biomarkers that may guide therapeutic decisions in refractory TGCTs.
The IPFSG (International Prognostic Factor Study Group) score relies on six clinical variables (primary tumor site, initial response to treatment, platinum-free interval, visceral metastases, and serum levels of HCG and AFP). It stratifies patients into five prognostic groups ranging from very good to very poor. Although clinically meaningful, this score does not account for the high molecular heterogeneity of TGCTs.
TGCTs exhibit a low global mutational burden (0.5 mutation/Mb), yet certain genetic alterations—such as TP53 mutations and MDM2 amplification—have been linked to cisplatin resistance. A gain at chromosome 3p25.3 has also been identified as an independent marker of poor prognosis, associated with more aggressive disease, particularly in mediastinal tumors.
Other factors include global DNA hypermethylation, epigenetic modifications affecting the polycomb complex (EZH2, SUZ12), and impaired double-strand break repair. These findings support a connection between epigenetic deregulation and chemoresistance, paving the way for targeted therapy using hypomethylating agents.
miR-371-3 and the miR-302/367 cluster are emerging as highly promising biomarkers, with circulating levels correlating with tumor burden, volume, treatment response, and relapse. The M371 test, based on measuring circulating miR-371a-3p, demonstrates a sensitivity of 90% and a specificity of 94% for TGCT detection, outperforming conventional tumor markers (AFP and HCG) for post-treatment monitoring.
Other miRNAs such as miR-302a, miR-106b, and miR-383 sensitize cells to cisplatin, whereas miR-512-3p and miR-525-3p are linked to resistance. These expression patterns could become actionable levers for personalized therapy.
Immune checkpoint inhibitors have shown limited efficacy in TGCTs due to the low tumor mutational burden. Yet high PD-L1 expression on tumor-infiltrating lymphocytes (TILs) correlates with better prognosis. Additional biomarkers under investigation include TIGIT, LAG-3, and TIM-3.
The Systemic Immune-Inflammation Index (SII)—based on markers such as CRP, neutrophils, and albumin—is also associated with a higher risk of recurrence and may support patient monitoring after treatment.
Emerging therapies
Phase I trials evaluating CAR-T cells targeting claudin-6 (CLDN6) in patients with advanced TGCTs have reported objective response rates (ORR) of 57%. Although preliminary, these results open the door to integrating cell-based therapies into the management of resistant TGCTs.
Salvage therapies can achieve long-term remission in a subset of patients, but a high-risk group continues to experience relapses. This review emphasizes the need to integrate molecular, epigenetic, immune, and inflammatory biomarkers into therapeutic decision-making. Genomic profiling and miRNA analysis are emerging as central tools for precision oncology.
In the short term, incorporating the M371 test into clinical practice may transform patient monitoring. In the medium term, combining clinical scores such as the IPFSG with molecular biomarkers could enable robust predictive algorithms. Finally, immunotherapies and CAR-T cell approaches may offer effective salvage options for the most resistant disease forms.
About the author – Lila Rouland
With dual expertise in science and marketing, Lila brings her knowledge to the service of healthcare innovation. After five years in international academic research, she transitioned into medical and scientific communication within the pharmaceutical industry. Now working as a medical writer and content developer, she is committed to highlighting scientific knowledge and conveying it to healthcare professionals with clarity and relevance.
Metastatic testicular germ cell tumors (TGCTs) currently achieve high cure rates with cisplatin-based chemotherapy; however, 20–30% of patients relapse or exhibit resistance to first-line treatment. For those facing refractory or relapsed disease, the identification of prognostic and predictive biomarkers is becoming essential to optimize salvage strategies, including conventional chemotherapy or high-dose regimens followed by autologous stem-cell transplantation.
The clinical parameters currently used (histology, tumor markers, clinical features) remain insufficient for predicting treatment response. This 2023 review summarizes current knowledge on molecular biomarkers that may guide therapeutic decisions in refractory TGCTs.
Could cisplatin resistance be overcome by biomarker-guided therapy?
The IPFSG (International Prognostic Factor Study Group) score relies on six clinical variables (primary tumor site, initial response to treatment, platinum-free interval, visceral metastases, and serum levels of HCG and AFP). It stratifies patients into five prognostic groups ranging from very good to very poor. Although clinically meaningful, this score does not account for the high molecular heterogeneity of TGCTs.
TGCTs exhibit a low global mutational burden (0.5 mutation/Mb), yet certain genetic alterations—such as TP53 mutations and MDM2 amplification—have been linked to cisplatin resistance. A gain at chromosome 3p25.3 has also been identified as an independent marker of poor prognosis, associated with more aggressive disease, particularly in mediastinal tumors.
Other factors include global DNA hypermethylation, epigenetic modifications affecting the polycomb complex (EZH2, SUZ12), and impaired double-strand break repair. These findings support a connection between epigenetic deregulation and chemoresistance, paving the way for targeted therapy using hypomethylating agents.
miRNAs: toward a new era of non-invasive biomarkers
miR-371-3 and the miR-302/367 cluster are emerging as highly promising biomarkers, with circulating levels correlating with tumor burden, volume, treatment response, and relapse. The M371 test, based on measuring circulating miR-371a-3p, demonstrates a sensitivity of 90% and a specificity of 94% for TGCT detection, outperforming conventional tumor markers (AFP and HCG) for post-treatment monitoring.
Other miRNAs such as miR-302a, miR-106b, and miR-383 sensitize cells to cisplatin, whereas miR-512-3p and miR-525-3p are linked to resistance. These expression patterns could become actionable levers for personalized therapy.
Immune biomarkers and inflammation
Immune checkpoint inhibitors have shown limited efficacy in TGCTs due to the low tumor mutational burden. Yet high PD-L1 expression on tumor-infiltrating lymphocytes (TILs) correlates with better prognosis. Additional biomarkers under investigation include TIGIT, LAG-3, and TIM-3.
The Systemic Immune-Inflammation Index (SII)—based on markers such as CRP, neutrophils, and albumin—is also associated with a higher risk of recurrence and may support patient monitoring after treatment.
Emerging therapies
Phase I trials evaluating CAR-T cells targeting claudin-6 (CLDN6) in patients with advanced TGCTs have reported objective response rates (ORR) of 57%. Although preliminary, these results open the door to integrating cell-based therapies into the management of resistant TGCTs.
Will biomarkers finally deliver true precision medicine in germ cell tumors?
Salvage therapies can achieve long-term remission in a subset of patients, but a high-risk group continues to experience relapses. This review emphasizes the need to integrate molecular, epigenetic, immune, and inflammatory biomarkers into therapeutic decision-making. Genomic profiling and miRNA analysis are emerging as central tools for precision oncology.
In the short term, incorporating the M371 test into clinical practice may transform patient monitoring. In the medium term, combining clinical scores such as the IPFSG with molecular biomarkers could enable robust predictive algorithms. Finally, immunotherapies and CAR-T cell approaches may offer effective salvage options for the most resistant disease forms.
Read next: Testicular Germ Cell Tumors: epidemiology, risk factors, and advances in management
About the author – Lila Rouland
Doctor of Oncology, specialized in Biotechnology and Management
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