Activation of the PI-3-Kinase Pathway and Prognostic Factors in Myxoid Liposarcoma.
Elizabeth G Demicco, Keila E Torres, Markus Ghadimi, Chiara Columbo, Tingsheng Peng, Dina Lev, Wei-Lien Wang, Alexander J Lazar. The University of Texas M.D. Anderson Cancer Center, Houston
Background: Myxoid liposarcoma (MLPS) is a common liposarcoma subtype. Hypercellularity evidenced by diffuse round cell (RC) change predicts a more agressive clinical course. Recently, several biomarkers have been proposed to have prognostic significance in MLPS, including Ki-67 and p53. It has also been shown that PI3KCA is mutated in 18% of MLPS resulting in activation of the PI3K/Akt pathway and poor prognosis. As this event represents a therapeutic target, we evaluated expression of phosphorylated downstream targets of the PI3K/Akt pathway (p6SRP and pEBP1) in a large series of MLPS with clinical follow-up to investigate the prevalence of activation of this pathway by mutation or other avenues.
Design: From our institutional prospective MPLS clinical database of 403 patients, 170 specimens from 111 patients with FFPE tissue were retrieved and formatted into a tissue microarray. Immunohistochemistry for Ki-67, p53, p6SRP and pEBP1 was performed and tabulated with clincopathologic details.
Results: The studied patient population (n=111) included 68 men and 43 women, with an age range of 17 – 79 years (median, 42). Primary sites included: lower extremity (78%), trunk (20%), and upper extremity (2%). Metastases evolved in 53 patients, sites included: retroperitoneum (42%), lung (21%), chest wall (21%), spine (11%), and flank (6%).
The TMA included 74 primaries, 60 metastases, and 24 recurrent tumors. 50 tumors showed histologic evidence of prior chemo- or radio-therapy. Nuclear Ki-67 expression was elevated (≥10%) in 20% of conventional MLPS and 39% of cellular/RC MLPS (p = 0.05), while nuclear p53 was overexpressed in 21% and 41% of these two groups, respectively (p = 0.05). Treated tumors had uniformly low Ki-67. Activation of the PI3K/Akt pathway was confirmed by immunoreactivity for p6SRP and pEBP1 in 55% and 62% of all cases, respectively. High expression of p6SRP was seen in 45% of conventional MLPS, 44% of cellular MLPS, and 84% of treated cases, while pEBP1 expression trended to association with cellular MLPS (81%), vs conventional (60%, p = 0.074) or treated (46%).
Conclusions: Expression of both Ki-67 and p53 correlated with aggressive histology. Significant expression of both p6SRP and pEBP1 confirmed activation of the PI3K/Akt pathway, where multiple inhibitors are in clinical trials, although p6SRP was not associated with aggressive histologic features. PI3KCA genotyping and correlation of biomarkers with clinical outcome in a multivariate analysis is ongoing.
Category: Bone & Soft Tissue
Monday, February 28, 2011 1:00 PM
Poster Session II # 26, Monday Afternoon