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RAS/MAPK hyperactivation may predict worse outcomes in undifferentiated pleomorphic sarcomas
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Hyperactivation of the RAS/mitogen-activated protein kinases pathway appeared to play a role in the aggressiveness of undifferentiated pleomorphic sarcomas, according to study results.
Thus, the RAS/mitogen-activated protein kinases (MAPK) pathway may be a significant prognostic factor for undifferentiated pleomorphic sarcomas, according to researchers.
The RAS/MAPK and phosphoinositide 3-kinase inhibitor (PI3K)/mammalian target of rapamycin (mTOR) pathways are known to be associated with sarcoma proliferation and survival; however, their role in undifferentiated pleomorphic sarcomas — the most common subtype of soft tissue sarcoma — had been poorly understood, according to study background.
Thus, César Serrano, MD, PhD, of the Translational Sarcoma Research Laboratory at Vall d’Hebron Institute of Oncology Vall d’Hebron University Hospital in Barcelona, and colleagues sought to determine if these pathways appeared activated in undifferentiated pleomorphic sarcomas and whether that activation is associated with outcome.
Researchers evaluated the records of 37 patients (59.6% men) who were diagnosed with undifferentiated pleomorphic sarcomas and treated at Vall d’Hebron University Hospital between 2000 and 2009. The median age of the cohort was 73 years (range, 32-96 years).
To analyze immunoexpression, the researchers collected a formalin-fixed, paraffin-embedded representative tumor tissue block from each patient and assessed them using immunohistochemistry. They evaluated the samples for the phosphorylation status of 4E-binding protein (4E-BP1), eukaryotic translation initiation factor (eIF-4E), S6-RP and ERK 1/2 using a Histo score, or a score from 0 to 3 based on the percentage of stained cells and the intensity of staining. Researchers also conducted mutational analysis for the following oncogenic mutations: KRAS, NRAS, BRAF and PIK3CA.
Researchers observed activation of critical lymph nodes in the RAS/MAPK and PI3K/mTOR pathways in at least 80% of patients. Immunohistochemistry analysis revealed expression — or a Histo score of at least 1 — of phospho-ERK 1/2 (86.5%), phospho-S6-RP (94.6%), phospho-4E-BP1 (94.4%), eIF-4E (100%) and phospho-eIF-4E (100%).
Results of a univariate analysis indicated high expression of phospho-ERK 1/2 was the only factor correlated with increased risk for post-surgical disease recurrence (HR = 3.32; 95% CI, 1.08-10.2). This association persisted in a controlled multivariable analysis (HR = 4.01; 95% CI, 1.28-12.6).
The only factors found to be independently predictive of poorer OS were hyperactivation levels of the RAS/MAPK pathway — as evaluated by phospho-ERK 1/2 expression — and high levels of the proliferation marker Ki-67. These findings were consistent in both univariate analysis (HR = 4.61; 95% CI, 1.04-20.5 for RAS/MAPK activation; HR = 5.6; 95% CI, 1.25-25.08 for elevated Ki-67 levels) and stepwise Cox multivariate analysis (HR = 6.95; 95% CI, 1.39-34.64 for RAS-MAPK hyperactivation; HR = 8.95; 95% CI, 1.79-44.7 for elevated Ki-67 levels).
These findings represent another great step toward better understanding of sarcoma biology, Rebecca D. Dodd, PhD, of the department of radiation oncology at Duke University, wrote in an accompanying editorial.
“The recent work by Serrano et al underscores the need to identify convergent signaling nodes in specific sarcoma subtypes,” Dodd wrote. “Moving onward, themes are emerging in the landscape of sarcoma biology that echo similar pathways found in other cancers. Sarcoma biologists can now begin the challenge of translating these findings into therapeutic benefit.” – by Jennifer Byrne
Disclosures: The researchers report no relevant disclosures.
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