title: High cytotoxic T-lymphocyte-associated antigen 4 and phospho-Akt expression in tumor samples predicts poor clinical outcomes in ipilimumab-treated melanoma patients.
abstract: Ipilimumab, a fully human monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), is the first immune checkpoint inhibitor approved for the treatment of unresectable melanoma on the basis of its overall survival (OS) benefit. However, ipilimumab is associated with significant immune-related adverse events. We hypothesized that biomarker exploration of pretreatment tumor samples and correlation with clinical outcome would enable patient selection with an increased benefit/risk ratio for ipilimumab therapy. At the University of Texas MD Anderson Cancer Center, a total of 81 advanced melanoma patients were treated on the Ipilimumab Expanded Access Program from 2007 to 2008. Using immunohistochemistry, we analyzed the expression of immune checkpoint (CTLA-4, PD-1, PD-L1) and Akt-pathway proteins in formalin-fixed tumor tissue. Associations between these biomarkers and progression-free survival (PFS) and OS were analyzed with univariate and multivariate Cox proportional-hazards models. There was a significant correlation between high CTLA-4 protein expression levels in tumor cells and risk of death (P=0.02) and decreased PFS (P=0.023). In addition, high expression of CTLA-4 in peritumoral lymphocytes correlated with poor OS (P=0.023). In multivariate analysis, patients with high CTLA-4 and phospho-Akt (p-Akt) expression correlated with poor OS (log-rank test, P=0.039) and PFS (log-rank test, P=0.014). High levels of CTLA-4 and p-Akt expression in pretreatment tumor cells in melanoma patients were associated with poor clinical outcomes. Immunohistochemistry analysis of CTLA-4 and p-Akt in pretreatment tumor samples provides useful biomarkers that may enable improved patient selection for ipilimumab therapy. Prospective clinical studies are warranted to investigate the predictive value of these biomarkers.
authors: Departments of aPathology bMelanoma Medical Oncology cBiostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: Nitin
authors: N
authors: Chakravarti
authors: Doina
authors: D
authors: Ivan
authors: Van A
authors: VA
authors: Trinh
authors: Isabella C
authors: IC
authors: Glitza
authors: Jonathan L
authors: JL
authors: Curry
authors: Carlos
authors: C
authors: Torres-Cabala
authors: Michael T
authors: MT
authors: Tetzlaff
authors: Roland L
authors: RL
authors: Bassett
authors: Victor G
authors: VG
authors: Prieto
authors: Wen-Jen
authors: WJ
authors: Hwu
mesh_terms: D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D060908:CTLA-4 Antigen / Q000378:metabolism*; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006305:Health Status Indicators; D006801:Humans; D000074324:Ipilimumab / Q000627:therapeutic use*; D007770:L-Lactate Dehydrogenase / Q000097:blood; D018655:Lymphocyte Count; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009367:Neoplasm Staging; D010766:Phosphorylation; D016016:Proportional Hazards Models; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D000074322:Antineoplastic Agents, Immunological; D014408:Biomarkers, Tumor; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000074324:Ipilimumab; D007770:L-Lactate Dehydrogenase; D051057:Proto-Oncogene Proteins c-akt