Abstract 415: Cytochrome CYP3A4 expression may predict metastasis in Ewing's sarcoma family of tumors.
Authors: Ahmed Atif , Zia Hamid , Murray Graeme I. , Vyhlidal Carrie A. , Leeder J. Steven , Bui Marilyn M. 
Published: August 2014

Background: Ewing's sarcoma family tumor (EFT) is an aggressive malignancy of bone and soft tissue with high incidence of metastasis and resistance to chemotherapy in metastatic disease. Cytochrome P450 (CYP) monooxygenases are a multigene family of enzymes that are involved in phase I reactions of metabolism of a wide range of endogenous compounds and xenobiotics, including anticancer drugs. Expression of CYP isoforms may influence tumor development, progression and resistance to therapy. Overexpression of CYP3A isoforms was associated with more aggressive behavior in breast cancer, osteosarcoma and other tumors. The purpose of this study is to define the expression CYP3A isoforms in EFT and establish its prognostic significance.

Design: Archived EFT cases and pertinent clinical data were compiled to include patient's age, sex, tumor location, tumor size, overall survival, disease-free survival and clinical stage. Two representative histologic sections of the tumors were selected for tissue microarray construction. Sections were processed for immunohistochemical labeling with CYP3A4, CYP3A5, and CYP3A7. Liver sections were used as positive control. The intensity of the staining was scored as negative, low (weak staining less than the positive control) or high (equal to or stronger than the positive control). The staining intensity was correlated with clinical data and the significance of any associations was statistically analyzed by one tailed and two tailed t-tests.

Results: 36 cases of Ewing sarcoma family of tumors were selected, 22 were males and 12 females. Age ranged from 12-72 years. 4 cases were excluded from immunohistochemical interpretation due inadequate viable tissue. CYP3A4 staining was present in 27 (84%) cases with high expression noted in 6 (19%) of 32 cases. High expression was significantly associated with distant metastases (p&lt; 0.05). There was no association of high CYP3A4 expression with age, sex, tumor size, or location (pelvic or extrapelvic). CYP3A5 and CYP3A7 were expressed in 5 and 13 cases (15.6%, 40.6%) respectively, and were not associated with age, sex, tumor size, metastasis or location. None of the studied biomarkers showed any correlation with overall or disease free survival.

Conclusion: CYP3A4, CYP3A5 and CYP3A7 are variably expressed in EFTs. High CYP3A4 expression may predict metastasis in EFT. Additional studies with higher number of cases are needed to further investigate the role of CYP3A4 in the prognosis of Ewing's sarcoma family tumors.

Citation Format: Atif Ahmed, Hamid Zia, Graeme I. Murray, Carrie A. Vyhlidal, J. Steven Leeder, Marilyn M. Bui. Cytochrome CYP3A4 expression may predict metastasis in Ewing's sarcoma family of tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 415. doi:10.1158/1538-7445.AM2013-415