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Published on: February 8, 2020
Molecular Subtypes of Clear-cell Renal Cell Carcinoma are Prognostic for Outcome After Complete Metastasectomy
Annelies Verbiest1, Gabrielle Couchy2, Sylvie Job3
1Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
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.
Insights
Clear-cell renal cell carcinoma (ccRCC) metastasectomy outcomes differ by molecular subtype. Patients with ccRCC subtypes 2 and 3 show longer disease-free survival after surgery compared to subtypes 1 and 4.
Area of Science:
- Oncology
- Genomics
- Surgical Oncology
Background:
- Metastasectomy is a standard treatment for select metastatic clear-cell renal cell carcinoma (ccRCC) patients.
- The prognostic value of ccRCC molecular subtypes (ccrcc1-4) in predicting outcomes after metastasectomy is not well-established.
- Previous research indicated prognostic and predictive value of these subtypes for systemic therapies.
Purpose of the Study:
- To evaluate the prognostic significance of the four ccRCC molecular subtypes (ccrcc1-4) following complete metastasectomy.
- To compare survival outcomes between good-prognosis (ccrcc2&3) and intermediate/poor-prognosis (ccrcc1&4) subtypes.
- To analyze survival differences among all four individual ccRCC subtypes post-metastasectomy.
Main Methods:
- Retrospective analysis of 43 ccRCC patients who underwent complete metastasectomy without systemic treatment.
- Molecular subtyping using a validated 35-gene expression classifier.
- Survival outcomes (DFS, time to systemic therapy, CSS, OS) analyzed using Kaplan-Meier and multivariable Cox regression.
Main Results:
- Patients with ccRCC subtypes 2&3 demonstrated significantly longer median disease-free survival (23 vs. 9 months), time to systemic therapy (92 vs. 28 months), cancer-specific survival (133 vs. 50 months), and overall survival (127 vs. 50 months) compared to subtypes 1&4.
- The prognostic value of the subtypes remained significant in multivariable analysis.
- Distinct survival differences were observed when comparing all four subtypes individually.
Conclusions:
- ccRCC molecular subtypes possess significant prognostic value after complete metastasectomy.
- Patients with ccRCC subtypes 1 or 4 face a higher risk of early relapse post-surgery.
- Subtypes 2 and 3 are associated with prolonged disease-free survival, suggesting potential benefit from metastasectomy.
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