Molecular Heterogeneity Between Paired Primary and Metastatic Lesions from Clear Cell Renal Cell Carcinoma

Highly effective systemic treatments have globally improved outcomes in metastatic clear-cell renal cell carcinoma (m-ccRCC). However, despite many efforts, reliable biomarkers predicting individual responses are currently lacking. Moreover, mixed responses are commonly observed. We hypothesized that molecular heterogeneity between primary tumors and their metastases could flaw biomarker research based on features of the primary tumor and explain mixed responses. Therefore, we studied the heterogeneity of the ccrcc1–4 molecular subtypes across patient-matched primary and metastatic lesions over time in 62 patients with m-ccRCC who underwent both nephrectomy and metastasectomy. These subtypes characterize underlying disease biology and are associated with outcomes in both the primary and metastatic settings. We observed a concordance rate of 58% (95% confidence interval 45–71%). This concordance was not affected by the interval between nephrectomy and resection of the metastatic lesion. Across discordant pairs, the metastatic lesions mostly exhibited a less favorable molecular subtype. Moreover, primary tumors with the favorable ccrcc2 molecular subtype were characterized by favorable prognosis and a long interval between nephrectomy and metastasectomy. Conversely, tumors with the unfavorable ccrcc4 molecular subtype relapsed quickly and had poor prognosis. Thus, the considerable molecular heterogeneity between patient-matched m-ccRCC primary and metastatic lesions provides an explanation for mixed responses to systemic therapy and could impact the development of biomarker studies in which the primary tumor is often considered a surrogate for metastatic disease. PATIENT SUMMARY: We studied primary tumors and metastases from patients with kidney cancer and found considerable heterogeneity in their molecular features. This heterogeneity explains mixed responses to systemic therapy and is important to take into account in future biomarker studies for this disease.