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Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 7/2016

01-07-2016 | Bone and Soft Tissue Sarcomas

Analysis of Clinical and Molecular Factors Impacting Oncologic Outcomes in Undifferentiated Pleomorphic Sarcoma

Authors: Christina L. Roland, MD, Caitlin D. May, PhD, Kelsey L. Watson, BS, Ghadah A. Al Sannaa, MD, Sean P. Dineen, MD, Rachel Feig, BS, Sharon Landers, PhD, Davis R. Ingram, BS, Wei-Lien Wang, MD, B. Ashleigh Guadagnolo, MD, Barry Feig, MD, Kelly K. Hunt, MD, Janice N. Cormier, MD, Alexander J. Lazar, MD, PhD, Keila E. Torres, MD, PhD

Published in: Annals of Surgical Oncology | Issue 7/2016

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Abstract

Background

Undifferentiated pleomorphic sarcomas (UPS) present a diagnostic and therapeutic challenge. Identification of prognostic molecular markers is required for the discovery of novel treatment approaches. The purpose of this study was to correlate clinicopathologic variables, expression of tyrosine kinase receptors, and markers of cell cycle progression and survival with oncologic outcomes.

Methods

A tissue microarray containing 208 primary UPS samples was analyzed by immunohistochemistry for protein markers and in situ hybridization for microRNA. Staining results were correlated with clinicopathologic features and oncologic outcomes. Univariate and multivariate analyses were conducted to assess associations between expression of protein markers, mi-RNA, and outcome.

Results

At a median follow-up of 3.9 years (9 years for survivors), 5-year disease-specific survival (DSS) was 63 %. Clinical variables associated with improved DSS included age <61 years, tumor size <10 cm, margin-negative resection, and sporadic-tumor status. At the protein level, loss of cyclin D1 (p = 0.06), pEGFR (p = 0.023), pIGF-1R (p = 0.022), and PTEN (p < 0.001) and overexpression of AXL (p = 0.015) were associated with reduced DSS on univariate analysis. Ki67, PCNA, and pEGFR were more highly expressed in sporadic UPS than radiation-associated (RA-UPS), whereas RA-UPS samples expressed higher levels of both phosphorylated and total IGF-1R.

Discussion

Loss of cyclin D1, overexpression of AXL, and loss of PTEN are associated with poor cancer-specific outcomes and warrant further investigation in UPS. The differences in protein expression in sporadic versus RA-UPS may indicate that the activated molecular signaling nodes may be different for each specific histology and also could explain the aggressive phenotype seen in RA-UPS compared with the sporadic lesions.
Literature
1.
Fletcher C, Bridge J, Hogendoorn P, Mertens F. WHO classification of tumours of soft tissue and bone. Lyon: IARC 2013.
2.
Delisca GO, Mesko NW, Alamanda VK, et al. MFH and high-grade undifferentiated pleomorphic sarcoma-what’s in a name? J Surg Oncol. 2015;111(2):173–7.CrossRefPubMed
3.
Mullen JT, Kobayashi W, Wang JJ, et al. Long-term follow-up of patients treated with neoadjuvant chemotherapy and radiotherapy for large, extremity soft tissue sarcomas. Cancer. 2012;118(15):3758–65.CrossRefPubMed
4.
Dineen SP, Roland CL, Feig R, et al. Radiation-associated undifferentiated pleomorphic sarcoma is associated with worse clinical outcomes than sporadic lesions. Ann Surg Oncol. 2015.
5.
Pervaiz N, Colterjohn N, Farrokhyar F, Tozer R, Figueredo A, Ghert M. A systematic meta-analysis of randomized controlled trials of adjuvant chemotherapy for localized resectable soft-tissue sarcoma. Cancer. 2008;113(3):573–81.CrossRefPubMed
6.
Sarcoma Meta-analysis Collaboration. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Lancet. 1997;350(9092):1647–54.
7.
Beane JD, Yang JC, White D, Steinberg SM, Rosenberg SA, Rudloff U. Efficacy of adjuvant radiation therapy in the treatment of soft tissue sarcoma of the extremity: 20-year follow-up of a randomized prospective trial. Ann Surg Oncol. 2014;21(8):2484–9.CrossRefPubMed
8.
Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol. 1998;16(1):197–203.PubMed
9.
Silveira SM, Villacis RA, Marchi FA, et al. Genomic signatures predict poor outcome in undifferentiated pleomorphic sarcomas and leiomyosarcomas. PloS One. 2013;8(6):e67643.CrossRefPubMedPubMedCentral
10.
Villacis RA, Silveira SM, Barros-Filho MC, et al. Gene expression profiling in leiomyosarcomas and undifferentiated pleomorphic sarcomas: SRC as a new diagnostic marker. PloS One. 2014;9(7):e102281.CrossRefPubMedPubMedCentral
11.
Takahashi A, Nakayama R, Ishibashi N, et al. Analysis of gene expression profiles of soft tissue sarcoma using a combination of knowledge-based filtering with integration of multiple statistics. PloS One. 2014;9(9):e106801.CrossRefPubMedPubMedCentral
12.
Ruping K, Altendorf-Hofmann A, Chen Y, et al. High IGF2 and FGFR3 are associated with tumour progression in undifferentiated pleomorphic sarcomas, but EGFR and FGFR3 mutations are a rare event. J Cancer Res Clin Oncol. 2014;140(8):1315–22.CrossRefPubMed
13.
Tomita Y, Morooka T, Hoshida Y, et al. Prognostic significance of activated AKT expression in soft-tissue sarcoma. Clin Cancer Res. 2006;12(10):3070–7.CrossRefPubMed
14.
Lahat G, Zhang P, Zhu QS, et al. The expression of c-Met pathway components in unclassified pleomorphic sarcoma/malignant fibrous histiocytoma (UPS/MFH): a tissue microarray study. Histopathology. 2011;59(3):556–61.CrossRefPubMed
15.
Nakatani F, Ferracin M, Manara MC, et al. miR-34a predicts survival of Ewing’s sarcoma patients and directly influences cell chemo-sensitivity and malignancy. J Pathol. 2012;226(5):796–805.CrossRefPubMed
16.
Sarver AL, Li L, Subramanian S. MicroRNA miR-183 functions as an oncogene by targeting the transcription factor EGR1 and promoting tumor cell migration. Cancer Res. 2010;70(23):9570–80.CrossRefPubMed
17.
Yu H, Lu Y, Li Z, Wang Q. microRNA-133: expression, function and therapeutic potential in muscle diseases and cancer. Current Drug Targets. 2014;15(9):817–28.CrossRefPubMed
18.
Sachdeva M, Mito JK, Lee CL, et al. MicroRNA-182 drives metastasis of primary sarcomas by targeting multiple genes. J Clin Invest. 2014;124(10):4305–19.CrossRefPubMedPubMedCentral
19.
Wong P, Hui A, Su J, et al. Prognostic microRNAs modulate the RHO adhesion pathway: A potential therapeutic target in undifferentiated pleomorphic sarcomas. Oncotarget. 2015;6(36):39127–39.PubMedPubMedCentral
20.
Lusby K, Savannah KB, Demicco EG, et al. Uterine leiomyosarcoma management, outcome, and associated molecular biomarkers: a single institution’s experience. Ann Surg Oncol. 2013;20:2364–72.CrossRefPubMedPubMedCentral
21.
Lahat G, Tuvin D, Wei C, et al. Molecular prognosticators of complex karyotype soft tissue sarcoma outcome: a tissue microarray-based study. Ann Oncol. 2010;21(5):1112–20.CrossRefPubMed
22.
Jorgensen S, Baker A, Moller S, Nielsen BS. Robust one-day in situ hybridization protocol for detection of microRNAs in paraffin samples using LNA probes. Methods. 2010;52(4):375–81.CrossRefPubMed
23.
Davis WJ, Lehmann PZ, Li W. Nuclear PI3K signaling in cell growth and tumorigenesis. Frontiers Cell Develop Biol. 2015;3:24.CrossRef
24.
Brennan MF, Antonescu CR, Maki RG. Management of soft tissue sarcoma. New York: Springer 2013.CrossRef
25.
Lehnhardt M, Daigeler A, Homann HH, et al. MFH revisited: outcome after surgical treatment of undifferentiated pleomorphic or not otherwise specified (NOS) sarcomas of the extremities: an analysis of 140 patients. Langenbeck’s Arch Surg. 2009;394(2):313–20.CrossRef
26.
Gladdy RA, Qin LX, Moraco N, et al. Do radiation-associated soft tissue sarcomas have the same prognosis as sporadic soft tissue sarcomas? J Clin Oncol. 2010;28(12):2064–9.CrossRefPubMedPubMedCentral
27.
28.
29.
Chu EC, Tarnawski AS. PTEN regulatory functions in tumor suppression and cell biology. Med Sci Monit. 2004;10(10):RA235-41.PubMed
30.
Niemeyer BF, Parrish JK, Spoelstra NS, Joyal T, Richer JK, Jedlicka P. Variable expression of PIK3R3 and PTEN in Ewing Sarcoma impacts oncogenic phenotypes. PloS One. 2015;10(1):e0116895.CrossRefPubMedPubMedCentral
31.
Gibault L, Perot G, Chibon F, et al. New insights in sarcoma oncogenesis: a comprehensive analysis of a large series of 160 soft tissue sarcomas with complex genomics. J Pathol. 2011;223(1):64–71.CrossRefPubMed
32.
Han J, Tian R, Yong B, et al. Gas6/Axl mediates tumor cell apoptosis, migration and invasion and predicts the clinical outcome of osteosarcoma patients. Biochem Biophys Res Comm. 2013;435(3):493–500.CrossRefPubMed
33.
Liu R, Gong M, Li X, et al. Induction, regulation, and biologic function of Axl receptor tyrosine kinase in Kaposi sarcoma. Blood. 2010;116(2):297–305.CrossRefPubMedPubMedCentral
34.
Hutterer M, Knyazev P, Abate A, et al. Axl and growth arrest-specific gene 6 are frequently overexpressed in human gliomas and predict poor prognosis in patients with glioblastoma multiforme. Clin Cancer Res. 2008;14(1):130–8.CrossRefPubMed
35.
Fleuren ED, Hillebrandt-Roeffen MH, Flucke UE, et al. The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma. Oncotarget. 2014;5(24):12753–68.CrossRefPubMedPubMedCentral
36.
Lee CH, Yen CY, Liu SY, et al. Axl is a prognostic marker in oral squamous cell carcinoma. Ann Surg Oncol. 2012;19 Suppl 3:S500-8.CrossRefPubMed
37.
Chen PX, Li QY, Yang Z. Axl and prostasin are biomarkers for prognosis of ovarian adenocarcinoma. Ann Diagn Pathol. 2013;17(5):425–9.CrossRefPubMed
38.
Sheridan C. First Axl inhibitor enters clinical trials. Nature Biotech. 2013;31(9):775–6.CrossRef
Metadata
Title
Analysis of Clinical and Molecular Factors Impacting Oncologic Outcomes in Undifferentiated Pleomorphic Sarcoma
Authors
Christina L. Roland, MD
Caitlin D. May, PhD
Kelsey L. Watson, BS
Ghadah A. Al Sannaa, MD
Sean P. Dineen, MD
Rachel Feig, BS
Sharon Landers, PhD
Davis R. Ingram, BS
Wei-Lien Wang, MD
B. Ashleigh Guadagnolo, MD
Barry Feig, MD
Kelly K. Hunt, MD
Janice N. Cormier, MD
Alexander J. Lazar, MD, PhD
Keila E. Torres, MD, PhD
Publication date
01-07-2016
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 7/2016
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-016-5115-5

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