Molecular Subtypes of Clear-cell Renal Cell Carcinoma are Prognostic for Outcome After Complete Metastasectomy

Eur Urol. 2018 Oct;74(4):474-480. doi: 10.1016/j.eururo.2018.01.042. Epub 2018 Feb 17.


Background: Metastasectomy is routinely performed in selected patients with metastatic clear-cell renal cell carcinoma (ccRCC) as an alternative to systemic therapy. In the absence of randomized trials, the benefit and best way of patient selection remain unclear. Earlier, we described four molecular ccRCC-subtypes (ccrcc1-4) that have a prognostic and predictive value upon first-line sunitinib or pazopanib.

Objective: Assess the prognostic value of ccrcc1-4 subtypes after complete metastasectomy. (1) Compare outcomes of good-prognosis ccrccc2&3-tumors with intermediate/poor-prognosis ccrcc1&4-tumors. (2) Compare outcomes of the four subtypes separately.

Design, setting, and participants: Single-center retrospective study (1995-2017), assessing 43 ccRCC patients undergoing complete metastasectomy without systemic treatment.

Intervention: Molecular subtype determined with established 35-gene expression classifier.

Outcome measurements and statistical analysis: Median disease-free survival (DFS), time to systemic therapy, cancer-specific (CSS) and overall survival (OS) from metastasectomy, estimated with Kaplan-Meier method and tested against other predictors with multivariable Cox regression.

Results and limitations: Median DFS was 23 mo for ccrcc2&3-tumors versus 9 mo for ccrcc1&4-tumors (p=0.011, hazard ratio [HR]=2.6). Median time to systemic therapy was 92 mo versus 28 mo (p=0.003, HR=3.3). Median CSS was 133 mo versus 50 mo (p<0.001, HR=2.7). Median OS was 127 mo versus 50 mo (p=0.011, HR=2.5). The classification remained independent upon multivariable analysis. Outcomes remained significantly different when comparing four subtypes separately. The intrinsic heterogeneity of expression profiles is a limitation of this approach.

Conclusion: Even after clinical patient selection, patients with a ccrcc1- or ccrcc4-tumor are at a higher risk of relapse after complete metastasectomy. Patients with a ccrcc2- or ccrcc3-tumor usually experience a long DFS. These results need validation in a larger cohort to establish the subtypes as prognostic marker.

Patient summary: Metastasectomy is recommended for some patients with metastatic clear-cell kidney cancer; however, we do not know who will benefit the most. We show that molecular subtypes increase the possibility to predict which patients are at risk for early relapse after metastasectomy and who may benefit more from other treatment options.

Keywords: Biomarker; Clear-cell renal cell carcinoma; Gene expression profile; Metastasectomy; Metastatic; Molecular subtypes; Prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Gland Neoplasms / pathology
  • Adrenal Gland Neoplasms / secondary
  • Adrenal Gland Neoplasms / surgery
  • Aged
  • Bone Neoplasms / pathology
  • Bone Neoplasms / secondary
  • Bone Neoplasms / surgery
  • Carcinoma, Renal Cell* / genetics
  • Carcinoma, Renal Cell* / pathology
  • Carcinoma, Renal Cell* / surgery
  • Cluster Analysis
  • Disease-Free Survival
  • Female
  • Gene Expression Profiling / methods*
  • Genetic Profile*
  • Humans
  • Kidney Neoplasms* / genetics
  • Kidney Neoplasms* / pathology
  • Kidney Neoplasms* / surgery
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary
  • Lung Neoplasms / surgery
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Outcome Assessment, Health Care
  • Prognosis
  • Signal Transduction / genetics*
  • Surgical Procedures, Operative / adverse effects
  • Surgical Procedures, Operative / classification
  • Surgical Procedures, Operative / methods