A significant number of patients fail to benefit from these therapies in the first line, underscoring the urgent need for predictive biomarkers to personalize treatment selection and improve clinical outcomes. However, existing molecular analyses must undergo thorough validation and refinement to ensure clinical robustness and transferability before their integration into routine workflows.
Transcriptomic analysis has emerged as a promising tool for stratifying patients and guiding therapy. The BIONIKK trial demonstrated the feasibility of selecting treatment based on transcriptomic phenotypes;3 however, challenges related to RNA biomarker robustness and consistency persist, and in particular the impact of tumor tissue origin has been neglected to date. Given the biological differences between primary tumors and metastatic sites, we conducted a post-hoc analysis of RNA sequencing data from over 1,000 patients across four clinical trials (IMmotion151, CheckMate 050/010/025). This analysis revealed that 266 genes were enriched in primary tumors and 348 genes in metastatic samples, with primary tumors showing upregulation of pathways related to p53, hypoxia, and TNFA. Importantly, the prognostic value of established molecular tissue clusters (MTCs) varied depending on the sample origin. For instance, MTC 4, associated with T-effector/proliferative characteristics, produced relatively consistent results regardless of tissue site, whereas MTC 2 (Angiogenic) and MTC 3 (Complement/-oxidative) demonstrated rather conflicting results between primary and metastatic samples.
For clinicians, a critical question arises: where is the most suitable tissue source for molecular analysis, and how should the results be interpreted? While primary tumor samples are more readily accessible and widely studied, they may fail to fully represent the lethal heterogeneity of mRCC. Conversely, metastatic tissue might offer valuable insights into treatment resistance and disease progression. However, as it is typically obtained via biopsies, it often contains only small parts of the metastases and considerable amounts of organ-specific non-tumorous material, complicating the interpretation. Thus, determining the optimal tissue site for biomarker testing is vital for advancing and refining treatment strategies.
The ongoing OPTIC trial evaluates the efficacy of current combination therapies based on pre-treatment RNA biomarkers. Tumor tissue from various anatomical sites is accepted for analysis.4 However, our findings suggest that the anatomical origin of tumor samples may significantly influence RNA biomarker results. To ensure more reliable conclusions, future clinical trials should incorporate detailed reporting of sample provenance and/or standardized trial protocols. This will enhance our understanding of organ-specific transcriptomic signatures and improve the clinical utility of RNA biomarkers
In conclusion, tumor sample origin plays a pivotal role in RNA biomarker research and its clinical application. Further studies are needed to determine whether primary or metastatic tissue—or even site-specific samples—are optimal for biomarker analysis. By addressing this critical variable, we might enhance the precision of biomarker-driven therapies, ultimately improving systemic treatment responses and survival outcomes for patients with mRCC and potentially other malignancies.
Written by: Lennert Eismann, MD, Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Urology, University Hospital Munich, LMU, Munich, Germany.
References:
- Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378(14):1277-90.
- Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021;384(14):1289-300.
- Vano YA, Elaidi R, Bennamoun M, Chevreau C, Borchiellini D, Pannier D, et al. Nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors as first-line treatment for metastatic clear-cell renal cell carcinoma (BIONIKK): a biomarker-driven, open-label, non-comparative, randomised, phase 2 trial. Lancet Oncol. 2022;23(5):612-24.
- Haake SM, Beckermann K, Chen Y-W, Reddy A, Mar N, Ornstein MC, et al. Initial screening efforts for the OPTIC RCC trial. Journal of Clinical Oncology. 2024;42(4_suppl):478-.