Many patients experience excellent long-term survival after treatment of clinically localized clear cell renal cell carcinoma (ccRCC). However, approximately 30% of patients with localized ccRCC may ultimately develop recurrent or metastatic disease after nephrectomy.¹ As adjuvant therapy for ccRCC continues to be an active area of research, with 1 treatment U.S. Food and Drug Administration approved,^2,3 appropriate patient selection for these therapies is key. Current prognostic markers for metastatic progression after radical nephrectomy for localized ccRCC include clinicopathological features such as tumor stage and grade. However, these risk factors do not capture the unique molecular landscape of the patient’s tumor. The addition of genomic tumor characteristics in a prognostic score may improve risk stratification and patient selection for enhanced follow-up strategies or adjuvant therapies.

Table. Patient Clinical Characteristics According to Recurrence Status

In prior work using The Cancer Genome Atlas ccRCC data, our group developed a 22-gene epithelial mesenchymal transition (EMT) score that was independently associated with poor progression-free and disease-specific survival.⁴ In this ongoing study, we retrospectively identified consecutive patients with ccRCC who underwent radical nephrectomy for localized disease. Those who developed metastasis were identified. We then performed whole-transcriptome mRNA sequencing of their primary tumor. Using this data, we conducted gene set enrichment analysis to identify significant cancer hallmark pathways enriched in patients who did compared to those who did not develop metastasis. Then, for each patient, the 22-gene EMT score was calculated and classified into high vs low risk as previously described.⁴ The prognostic impact of the EMT score was evaluated by performing multivariable cox-proportional hazard testing and Kaplan-Meier survival analysis.

In the present study, we analyzed 82 patients with a median age of 62 years and a median tumor size of 6 ± 2.9 cm. The median time to metastasis after radical nephrectomy for patients who developed metastasis (n = 13) was 17 months and median follow-up 32 months for patients who did not develop metastasis (n = 68; see Table). We observed a significant enrichment of EMT, myogenesis, inflammatory response and hypoxia hallmark pathways in patients with metastasis vs those without metastasis. Kaplan-Meier survival analysis showed shorter metastasis-free survival in patients with a high EMT score (p = 0.018; see Figure) compared to a low EMT score. Multivariable analysis controlling for relevant clinicopathological features including age, sex, tumor size, tumor stage, lymphovascular invasion, and necrosis revealed high EMT score to be independently associated with the development of metastasis (HR 7.2; 95% CI 1.15-44.8; P = .035).

By analyzing the patient’s primary tumor, our tissue-based 22-gene EMT score predicted future development of metastasis in patients treated with radical nephrectomy for localized ccRCC. Pending further validation studies, the EMT score may improve risk stratification beyond clinicopathological features and allow for a more nuanced approach to patient counseling, follow-up, or adjuvant therapies.