Serum lactate dehydrogenase predicts for overall survival benefit in patients with metastatic renal cell carcinoma treated with inhibition of mammalian target of rapamycin.
OBJECTIVE
Lactate dehydrogenase (LDH) is an enzyme involved in anaerobic glycolysis and regulated by the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR)-containing complex 1 (PI3K/Akt/TORC1) pathway as well as tumor hypoxia/necrosis. High serum LDH levels are associated with poor prognosis in patients with cancer, including renal cell carcinoma (RCC). We tested whether serum LDH is prognostic and has predictive value in patients with metastatic RCC receiving an mTOR inhibitor.


METHODS
We evaluated pretreatment and post-treatment serum LDH in 404 poor-risk patients with RCC treated with the TORC1 inhibitor temsirolimus or interferon alfa in an international phase III randomized trial. The proportional hazards model was used to test for the prognostic and predictive association of LDH in predicting overall survival (OS).


RESULTS
Mean baseline serum normalized LDH was 1.23 times the upper limit of normal (ULN; range, 0.05 to 28.5 × ULN). The multivariable hazard ratio for death was 2.81 (95% CI, 2.01 to 3.94; P < .001) for patients with LDH more than 1 × ULN versus patients with LDH ≤ 1 × ULN. The LDH-treatment interaction term was statistically significant for OS (P = .016). Among 140 patients with LDH above the ULN, OS was significantly improved with temsirolimus (6.9 v 4.2 months; P < .002). Among 264 patients with normal LDH, OS was not significantly improved with temsirolimus as compared with interferon therapy (11.7 v 10.4 months; P = .514).


CONCLUSIONS
Serum LDH is a prognostic and a predictive biomarker for the survival benefit conferred by TORC1 inhibition in poor-risk RCC. Further investigation of the predictive role of LDH as a measure of benefit with PI3K/TORC1 pathway inhibition in other RCC risk groups and other tumor types is warranted.
Divisions of Medical Oncology and Urology, Department of Medicine, Duke Cancer Institute, Duke University Medical Center, Box 102002, Durham, NC 27710, USA. andrew.armstrong@duke.edu
Andrew J
AJ
Armstrong
Daniel J
DJ
George
Susan
S
Halabi
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D054316:Biomarkers, Pharmacological / Q000097:blood*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000188:drug therapy*; D007770:L-Lactate Dehydrogenase / Q000097:blood*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012189:Retrospective Studies; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; C500984:CRTC1 protein, human; D016898:Interferon-alpha; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; C401859:temsirolimus; D007770:L-Lactate Dehydrogenase; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus