Re: 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.