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The evolving role of cytoreductive nephrectomy

incorporating genomics of metastatic renal cell carcinoma into treatment decisions

Mano, Roya; Gopal, Nikhilb; Hakimi, A. Aria

doi: 10.1097/MOU.0000000000000663
EVOLVING ROLE OF CYTOREDUCTIVE NEPHRECTOMY: Edited by Vitaly Margulis and A. Ari Hakimi
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Purpose of review Recent publications evaluating cytoreductive nephrectomy in the era of targeted therapy emphasize the importance of patient selection. We reviewed the predictive role of genetic alterations in patients with metastatic renal cell carcinoma (mRCC) undergoing cytoreductive nephrectomy.

Recent findings Studies evaluating the association between genetic alterations and outcomes following systemic treatment for mRCC include mainly patients after cytoreductive nephrectomy. Expression of proangiogenic genes, single nucleotide polymorphisms involving genes of the vascular-endothelial growth factor (VEGF) pathway and somatic mutations of chromatin remodeling genes were associated with response to VEGF-targeted therapy. Outcomes following treatment with mammalian target of rapamycin (mTOR) inhibitors were initially associated with mTOR/TSC1/TSC2 mutations; however, subsequent studies did not validate these findings but rather found an association between loss of PTEN expression and PBRM1 mutations and improved outcomes. Loss of PBRM1 was initially linked to response to immunotherapy; however, larger studies question this association and showed high expression of T-effector gene signature predicted improved outcome. Primary tumors with low intratumor heterogeneity but elevated somatic copy-number alterations were associated with rapid progression at multiple sites.

Summary Genetic alterations may help select patients for cytoreductive nephrectomy and optimize timing of treatment. Intratumor heterogeneity and genetic discordance between primary and metastatic tumors may limit clinical applicability. Future studies should evaluate approaches to overcome these limitations.

aUrology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York

bDepartment of Urology, New York Medical College, Valhalla, New York, USA

Correspondence to A. Ari Hakimi, MD, Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA. Tel: +1 646 422 4497; fax: +1 212 988 0760; e-mail: hakimia@mskcc.org

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