Prognostic and Predictive Markers in Metastatic Renal Cell Carcinoma

astatic renal cell carcinoma (mRCC) has been made over the last 5 years, with a plethora of targeted agents currently approved in different clinical settings. However, not all mRCC patients respond to treatment with these drugs and currently there are no validated biomarkers to predict clinical outcome. We therefore read with interest Armstrongetal’s 1 reportoftheprognosticandpredictivesignificance of baseline serum lactate dehydrogenase (LDH) in patients with intermediate- and-poor risk mRCC treated in a first-line trial of the mammalian target of rapamycin (mTOR) inhibitor temsirolimus, interferon-alfa, or both in combination. As expected, in multivariate analysis,overallsurvival(OS)wassignificantlyshorterinpatientswith LDHmorethan1theupperlimitofnormal(ULN)comparedwith patients with LDH 1ULN at baseline. The importance of a high baseline LDH as a predictor of response to temsirolimus was also examined: in patients with LDH more than ULN, median OS with temsirolimus was 6.9 months versus 4.2 months with interferon-alfa (hazard ratio, 0.56; 95% CI, 0.38 to 0.81; P .002). There was no difference in risk of death between temsirolimus and interferon-alfa treatment in patients with normal LDH. However, patients with an elevatedLDHinthistrialweremorelikelytobeofpoorriskbyMotzer criteria and it is unlikely that interferon-alfa provided any benefit in this group 2 and, given the associated toxicity, it may even have been detrimental. Survival comparisons between temsirolimus and interferon-alfa should therefore be viewed with caution. The prognostic impact of baseline LDH was evaluated in the RECORD-1(Renal Cell Cancer Treatment With Oral RAD001 Given Daily) trial of the mTOR inhibitor everolimus in mRCC refractory to anti‐vascular endothelial growth factor (VEGF) therapy. 3 High LDH was found to be prognostic for OS, but not progression free survival (PFS)inunivariateanalysis,butitwasnotincludedinthefinalmodel of multivariate analysis because of its nonlinear effect. High pretreatmentLDHishoweveraprognosticmarkerforbothPFSandOSinthe first-line setting during treatment with the VEGF receptor tyrosine kinase inhibitor sunitinib and interferon-alfa in predominantly good or intermediate risk (93%) mRCC 4 as well as for OS in the sunitinibrefractory setting during treatment with the VEGF receptor tyrosine kinase inhibitor axitinib. 5 To examine further the relationship betweenprognosisandLDHduringeverolimustherapy,weevaluatedall