Complete loss of PTEN protein expression correlates with shorter time to brain metastasis and survival in stage IIIB/C melanoma patients with BRAF mutations

Purpose: Loss of function of PTEN is a frequent event inmelanoma, particularly in tumorswithBRAF mutations. The prevalence, pathologic features, and clinical outcomes associated with PTEN loss in patients with stage IIIB/C melanoma were interrogated to improve our understanding of the clinical significance of this molecular event. ExperimentalDesign:Archival tissue from lymphadenectomy specimens amongpatients (n1⁄4136)with stage IIIB or IIICmelanomawas assessed byDNA sequencing for activating BRAF andNRASmutations, and by immunohistochemistry for the expression of PTEN protein. Associations of these molecular aberrations with demographics, tumor characteristics, and clinical outcomes were determined. Results: The prevalence of BRAF mutations (40% overall), NRAS mutations (10%), and PTEN loss (25%) did not vary by pathologic substage. BRAF/NRAS mutation status did not correlate with distant disease-free survival (DDFS) or overall survival (OS). Complete loss of PTEN expression correlated with shorter OS but not DDFS. When stratified by specific sites of distant metastasis, PTEN loss was associated with significantly shorter time to melanoma brain metastasis (MBM), but not to liver, lung, or bone metastasis. Analysis of PTEN in mutationally defined subsets showed that PTEN loss was significantly associated with OS and time to MBM in patients with BRAF mutations. Conclusions: Loss of PTEN protein expression correlates significantly with decreased OS and time to MBM in stage IIIB/C melanoma patients with BRAF mutations. The findings add to evidence supporting a significant role for PTEN loss and the PI3K–AKT pathway in melanoma. Clin Cancer Res; 20(21); 5527–36. 2014 AACR.