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BACKGROUND Undifferentiated pleomorphic sarcoma (UPS) constitutes the most common subtype of soft tissue sarcoma. However, UPS is clinically and molecularly poorly understood, in great extent due to its intrinsic phenotypic and cytogenetic complexity, which in turn results in the absence of specific prognostic or predictive biomarkers. The RAS/mitogen‐activated protein kinases (MAPK) and phosphoinositide 3‐kinase inhibitor (PI3K)/mammalian target of rapamycin (mTOR) pathways are considered to be 2 major mechanisms for sarcoma proliferation and survival and to the authors' knowledge their role in UPS remains unclear. The objective of the current study was to investigate whether the RAS/MAPK and PI3K/mTOR pathways are activated in UPS, and whether pathway activation is associated with outcome. METHODS Records for patients diagnosed and treated for UPS in the study institution between 2000 and 2009 were reviewed. Phosphorylation status of 4E‐binding protein (4E‐BP1), eukaryotic translation initiation factor 4E (eIF‐4E), S6‐RP, and ERK 1/2, together with total forms of 4E‐BP1 and eIF‐4E, were assessed using immunohistochemistry in paraffin‐embedded tumor tissue. Mutational analysis for KRAS; NRAS; BRAF; and phosphatidylinositol‐4,5‐bisphosphate 3‐kinase, catalytic subunit alpha (PIK3CA) oncogenic mutations was performed as well. RESULTS Critical lymph nodes within the RAS/MAPK and PI3K/mTOR pathways were found to be activated in >80% of UPS cases. Hyperactivation of the RAS/MAPK pathway, as assessed by expression of phosphorylated ERK 1/2, was found to independently predict a higher risk of disease recurrence and impaired overall survival. Only a KRAS A146V mutation was detected in 1 tumor. CONCLUSIONS The RAS/MAPK and PI3K/mTOR pathways are activated in the majority of cases of UPS. The RAS/MAPK pathway distinguishes a subgroup of patients with localized UPS with a worse outcome. Cancer 2016;122:99–107. © 2015 American Cancer Society.

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