By Lila Rouland | Published on December 1rst, 2025 | 3 min readMetastatic 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 RoulandDoctor of Oncology, specialized in Biotechnology and Management
