Clear Cell Type A and B Molecular Subtypes in Metastatic Clear Cell Renal Cell Carcinoma: Tumor Heterogeneity and Aggressiveness.

BACKGROUND: Intratumor molecular heterogeneity has been reported for primary clear cell renal cell carcinoma (ccRCC) tumors; however, heterogeneity in metastatic ccRCC tumors has not been explored.
OBJECTIVE: To evaluate intra- and intertumor molecular heterogeneity in resected metastatic ccRCC tumors. DESIGN, SETTING, AND PARTICIPANTS: We identified 111 patients who had tissue available from their primary tumor and at least one metastasis. ClearCode34 genes were analyzed for all tumors. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary and metastatic tumors were classified as clear cell type A (ccA) or B (ccB) subtypes. Logistic and Cox regression were used to evaluate associations with pathologic features and survival. RESULTS AND LIMITATIONS: Intratumor heterogeneity of ccA/ccB subtypes was observed in 22% (95% confidence interval [CI] 3-60%) of metastatic tumors. Subtype differed across longitudinal metastatic tumors from the same patient in 23% (95% CI 10-42%) of patients and across patient-matched primary and metastatic tumors in 43% (95% CI 32-55%) of patients. Association of subtype with survival was validated in primary ccRCC tumors. The ccA/ccB subtype in metastatic tumors was significantly associated with metastatic tumor location, metastatic tumor grade, and presence of tumor necrosis. A limitation of this study is that we only analyzed patients who had both a nephrectomy and metastasectomy.
CONCLUSIONS: Approximately one quarter of metastatic tumors displayed intratumor heterogeneity; a similar rate of heterogeneity was observed across longitudinal metastatic tumors. Thus, for biomarker studies it is likely adequate to analyze a single sample per metastatic tumor provided that pathologic review is incorporated into the study design. Subtypes across patient-matched primary and metastatic tumors differed 43% of the time, suggesting that the primary tumor is not a good surrogate for the metastatic tumor. PATIENT
SUMMARY: Primary and secondary/metastatic cancers of the kidney differed in nearly one half of ccRCC patients. The pattern of this relationship may affect tumor growth and the most suitable treatment.