Correlation of High-Risk Soft Tissue Sarcoma Biomarker Expression Patterns with Outcome following Neoadjuvant Chemoradiation

John M Kane 3rd, Anthony Magliocco, Qiang Zhang, Dian Wang, Alex Klimowicz, Jonathan Harris, Jeff Simko, Thomas DeLaney, William Kraybill, David G Kirsch, John M Kane 3rd, Anthony Magliocco, Qiang Zhang, Dian Wang, Alex Klimowicz, Jonathan Harris, Jeff Simko, Thomas DeLaney, William Kraybill, David G Kirsch

Abstract

Background: Sarcoma mortality remains high despite adjuvant chemotherapy. Biomarker predictors of treatment response and outcome could improve treatment selection.

Methods: Tissue microarrays (TMAs) were created using pre- and posttreatment tumor from two prospective trials (MGH pilot and RTOG 9514) of neoadjuvant/adjuvant MAID chemotherapy and preoperative radiation. Biomarkers were measured using automated computerized imaging (AQUA or ACIS). Expression was correlated with disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS).

Results: Specimens from 60 patients included 23 pretreatment (PRE), 40 posttreatment (POST), and 12 matched pairs (MPs). In the MP set, CAIX, GLUT1, and PARP1 expression significantly decreased following neoadjuvant therapy, but p53 nuclear/cytoplasmic (N/C) ratio increased. In the PRE set, no biomarker expression was associated with DFS, DDFS, or OS. In the POST set, increased p53 N/C ratio was associated with a significantly decreased DFS and DDFS (HR 4.13, p=0.017; HR 4.16, p=0.016), while increased ERCC1 and XPF expression were associated with an improved DFS and DDFS. No POST biomarkers were associated with OS.

Conclusions: PRE biomarker expression did not predict survival outcomes. Expression pattern changes after neoadjuvant chemoradiation supports the concepts of tumor reoxygenation, altered HIF-1α signaling, and a p53 nuclear accumulation DNA damage response.

Clinical trial registration: NRG Oncology RTOG 9514 is registered with ClinicalTrials.gov. The ClinicalTrials.gov Identifier is NCT00002791.

Figures

Figure 1
Figure 1
Kaplan-Meier estimates for disease-free survival, distant disease-free survival, and overall survival for deep, high-grade soft tissue sarcoma patients (with at least one biomarker value) treated with neoadjuvant chemoradiation.

References

    1. Sarcoma Meta-Analysis Collaboration. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma meta-analysis collaboration. The Lancet. 1997;350(9092):1647–1654.
    1. Frustaci S., Gherlinzoni F., De Paoli A., et al. Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: results of the Italian randomized cooperative trial. Journal of Clinical Oncology. 2001;19(5):1238–1247. doi: 10.1200/jco.2001.19.5.1238.
    1. 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):573–581. doi: 10.1002/cncr.23592.
    1. DeLaney T. F., Spiro I. J., Suit H. D., et al. Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. International Journal of Radiation Oncology, Biology, Physics. 2003;56(4):1117–1127. doi: 10.1016/s0360-3016(03)00186-x.
    1. Kraybill W. G., Harris J., Spiro I. J., et al. Phase II study of neoadjuvant chemotherapy and radiation therapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. Journal of Clinical Oncology. 2006;24(4):619–625. doi: 10.1200/JCO.2005.02.5577.
    1. Look Hong N. J., Hornicek F. J., Harmon D. C., et al. Neoadjuvant chemoradiotherapy for patients with high-risk extremity and truncal sarcomas: a 10-year single institution retrospective study. European Journal of Cancer. 2013;49(4):875–883. doi: 10.1016/j.ejca.2012.10.002.
    1. Kraybill W. G., Harris J., Spiro I. J., et al. Long-term results of a phase 2 study of neoadjuvant chemotherapy and radiotherapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514. Cancer. 2010;116(19):4613–4621. doi: 10.1002/cncr.25350.
    1. Gerdes J., Li L., Schlueter C., et al. Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67. American Journal of Pathology. 1991;138(4):867–873.
    1. Choong P. F., Akerman M., Willen H., et al. Prognostic value of Ki-67 expression in 182 soft tissue sarcomas. Proliferation–a marker of metastasis? APMIS. 1994;102(12):915–924. doi: 10.1111/j.1699-0463.1994.tb05253.x.
    1. Huuhtanen R. L., Blomqvist C. P., Wiklund T. A., et al. Comparison of the Ki-67 score and S-phase fraction as prognostic variables in soft-tissue sarcoma. British Journal of Cancer. 1999;79(5-6):945–951. doi: 10.1038/sj.bjc.6690151.
    1. Taubert H., Meye A., Wurl P. Soft tissue sarcomas and p53 mutations. Molecular Medicine. 1998;4(6):365–372.
    1. Taubert H., Wurl P., Bache M., et al. The p53 gene in soft tissue sarcomas: prognostic value of DNA sequencing versus immunohistochemistry. Anticancer Research. 1998;18(1):183–187.
    1. Wurl P., Taubert H., Meye A., et al. Prognostic value of immunohistochemistry for p53 in primary soft-tissue sarcomas: a multivariate analysis of five antibodies. Journal of Cancer Research and Clinical Oncology. 1997;123(9):502–508. doi: 10.1007/s004320050095.
    1. Lee J. H., Paull T. T. Activation and regulation of ATM kinase activity in response to DNA double-strand breaks. Oncogene. 2007;26(56):7741–7748. doi: 10.1038/sj.onc.1210872.
    1. Kastan M. B., Zhan Q., El-Deiry W. S., et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell. 1992;71(4):587–597. doi: 10.1016/0092-8674(92)90593-2.
    1. Schiewer M. J., Goodwin J. F., Han S., et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discovery. 2012;2(12):1134–1149. doi: 10.1158/-12-0120.
    1. Zaremba T., Thomas H., Cole M., Plummer E. R., Curtin N. J. Doxorubicin-induced suppression of poly(ADP-ribose) polymerase-1 (PARP-1) activity and expression and its implication for PARP inhibitors in clinical trials. Cancer Chemotherapy and Pharmacology. 2010;66(4):807–812. doi: 10.1007/s00280-010-1359-0.
    1. Kirschner K., Melton D. W. Multiple roles of the ERCC1-XPF endonuclease in DNA repair and resistance to anticancer drugs. Anticancer Research. 2010;30(9):3223–3232.
    1. Italiano A., Laurand A., Laroche A., et al. ERCC5/XPG, ERCC1, and BRCA1 gene status and clinical benefit of trabectedin in patients with soft tissue sarcoma. Cancer. 2011;117(15):3445–3456. doi: 10.1002/cncr.25925.
    1. Sly W. S., Hu P. Y. Human carbonic anhydrases and carbonic anhydrase deficiencies. Annual Review of Biochemistry. 1995;64(1):375–401. doi: 10.1146/annurev.bi.64.070195.002111.
    1. Wykoff C. C., Beasley N. J., Watson P. H., et al. Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Research. 2000;60(24):7075–7083.
    1. Maseide K., Kandel R. A., Bell R. S., et al. Carbonic anhydrase IX as a marker for poor prognosis in soft tissue sarcoma. Clinical Cancer Research. 2004;10(13):4464–4471. doi: 10.1158/1078-0432.CCR-03-0541.
    1. Vaupel P. The role of hypoxia-induced factors in tumor progression. Oncologist. 2004;9(5):10–17. doi: 10.1634/theoncologist.9-90005-10.
    1. Endo M., Tateishi U., Seki K., et al. Prognostic implications of glucose transporter protein-1 (glut-1) overexpression in bone and soft-tissue sarcomas. Japanese Journal of Clinical Oncology. 2007;37(12):955–960. doi: 10.1093/jjco/hym125.
    1. Semenza G. L. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. Journal of Applied Physiology. 2000;88(4):1474–1480. doi: 10.1152/jappl.2000.88.4.1474.
    1. Sullivan R., Graham C. H. Hypoxia-driven selection of the metastatic phenotype. Cancer and Metastasis Reviews. 2007;26(2):319–331. doi: 10.1007/s10555-007-9062-2.
    1. Eisinger-Mathason T. S., Zhang M., Qiu Q., et al. Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis. Cancer Discovery. 2013;3(10):1190–1205. doi: 10.1158/-13-0118.
    1. Shintani K., Matsumine A., Kusuzaki K., et al. Expression of hypoxia-inducible factor (HIF)-1 alpha as a biomarker of outcome in soft-tissue sarcomas. Virchows Archiv. 2006;449(6):673–681. doi: 10.1007/s00428-006-0304-4.
    1. Zhang M., Qiu Q., Li Z., et al. HIF-1 alpha regulates the response of primary sarcomas to radiation therapy through a cell autonomous mechanism. Radiation Research. 2015;183(6):594–609. doi: 10.1667/RR14016.1.
    1. Kononen J., Bubendorf L., Kallioniemi A., et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nature Medicine. 1998;4(7):844–847. doi: 10.1038/nm0798-844.
    1. Rubin M. A., Dunn R., Strawderman M., Pienta K. J. Tissue microarray sampling strategy for prostate cancer biomarker analysis. American Journal of Surgical Pathology. 2002;26(3):312–319. doi: 10.1097/00000478-200203000-00004.
    1. Otsuka S., Klimowicz A. C., Kopciuk K., et al. CXCR4 overexpression is associated with poor outcome in females diagnosed with stage IV non-small cell lung cancer. Journal of Thoracic Oncology. 2011;6(7):1169–1178. doi: 10.1097/JTO.0b013e3182199a99.
    1. Camp R. L., Chung G. G., Rimm D. L. Automated subcellular localization and quantification of protein expression in tissue microarrays. Nature Medicine. 2002;8(11):1323–1327. doi: 10.1038/nm791.
    1. Kallman R. F., Dorie M. J. Tumor oxygenation and reoxygenation during radiation therapy: their importance in predicting tumor response. International Journal of Radiation Oncology, Biology, Physics. 1986;12(4):681–685. doi: 10.1016/0360-3016(86)90080-5.
    1. Iyer N. V., Kotch L. E., Agani F., et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes & Development. 1998;12(2):149–162. doi: 10.1101/gad.12.2.149.
    1. Kaluz S., Kaluzova M., Liao S. Y., Lerman M., Stanbridge E. J. Transcriptional control of the tumor- and hypoxia-marker carbonic anhydrase 9: a one transcription factor (HIF-1) show? Biochimica et Biophysica Acta. 2009;1795(2):162–172. doi: 10.1016/j.bbcan.2009.01.001.
    1. Cao Y., Eble J. M., Moon E., et al. Tumor cells upregulate normoxic HIF-1 alpha in response to doxorubicin. Cancer Research. 2013;73(20):6230–6242. doi: 10.1158/0008-5472.CAN-12-1345.
    1. Moeller B. J., Cao Y., Li C. Y., Dewhirst M. W. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell. 2004;5(5):429–441. doi: 10.1016/s1535-6108(04)00115-1.
    1. Rodrigo R. S., Nathalie A., Elodie T., et al. Topoisomerase II-alpha protein expression and histological response following doxorubicin-based induction chemotherapy predict survival of locally advanced soft tissues sarcomas. European Journal of Cancer. 2011;47(9):1319–1327. doi: 10.1016/j.ejca.2011.02.010.
    1. Brustmann H. Poly(adenosine diphosphate-ribose) polymerase expression in serous ovarian carcinoma: correlation with p53, MIB-1, and outcome. International Journal of Gynecological Pathology. 2007;26(2):147–153. doi: 10.1097/.
    1. Goncalves A., Finetti P., Sabatier R., et al. Poly(ADP-ribose) polymerase-1 mRNA expression in human breast cancer: a meta-analysis. Breast Cancer Research and Treatment. 2011;127(1):273–281. doi: 10.1007/s10549-010-1199-y.
    1. Blagosklonny M. Loss of function and p53 protein stabilization. Oncogene. 1997;16(16):1889–1893. doi: 10.1038/sj.onc.1201374.
    1. Jackson J. G., Pant V., Li Q., et al. P53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. Cancer Cell. 2012;21(6):793–806. doi: 10.1016/j.ccr.2012.04.027.

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