Predictive Biomarkers and Personalized Medicine TMPRSS2-ERG Status Is Not Prognostic Following Prostate CancerRadiotherapy: Implications forFusionStatusandDSB Repair

Background: Preclinical data suggest that TMPRSS2-ERG gene fusions, present in about 50% of prostate cancers, may be a surrogate for DNA repair status and therefore a biomarker for DNA-damaging agents. To test this hypothesis, we examined whether TMPRSS2-ERG status was associated with biochemical failure after clinical induction of DNA damage following image-guided radiotherapy (IGRT). Methods: Pretreatment biopsies from two cohorts of patients with intermediate-risk prostate cancer [T1/T2, Gleason score (GS) < 8, prostate-specific antigen (PSA) < 20 ng/mL; >7 years follow-up] were analyzed: (i) 126 patients [comparative genomic hybridization (CGH) cohort] with DNA samples assayed by array CGH (aCGH) for the TMPRSS2-ERG fusion; and (ii) 118 patients [immunohistochemical (IHC) cohort] whose biopsy samples were scored within a defined tissue microarray (TMA) immunostained for ERGoverexpression (known surrogate for TMPRSS2-ERG fusion). Patients were treatedwith IGRTwith a median dose of 76 Gy. The potential role of TMPRSS2-ERG status as a prognostic factor for biochemical relapse-free rate (bRFR; nadir þ 2 ng/mL) was evaluated in the context of clinical prognostic factors in multivariate analyses using a Cox proportional hazards model. Results: TMPRSS2-ERG fusion by aCGHwas identified in 27 (21%) of the cases in the CGH cohort, and ERG overexpression was found in 59 (50%) patients in the IHC cohort. In both cohorts, TMPRSS2-ERG status was not associated with bRFR on univariate or multivariate analysis. Conclusions: In two similarly treated IGRT cohorts, TMPRSS2-ERG status was not prognostic for bRFR, in disagreement with the hypothesis that these prostate cancers have DNA repair defects that render them clinically more radiosensitive. TMPRSS2-ERG is therefore unlikely to be a predictive factor for IGRT response. Clin Cancer Res; 19(18); 5202–9. 2013 AACR.

[1]  M. Loda,et al.  ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients. , 2013, Genes & development.

[2]  G. Sauter,et al.  Marked heterogeneity of ERG expression in large primary prostate cancers , 2013, Modern Pathology.

[3]  A. Chinnaiyan,et al.  Dual roles of PARP-1 promote cancer growth and progression. , 2012, Cancer discovery.

[4]  P. Ghadjar,et al.  Comparative analysis of prostate‐specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group , 2012, BJU international.

[5]  Charles A Enke,et al.  Prostate cancer, Version 3.2012: featured updates to the NCCN guidelines. , 2012, Journal of the National Comprehensive Cancer Network : JNCCN.

[6]  T. H. van der Kwast,et al.  Copy number alterations of c‐MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy , 2012, Cancer.

[7]  Jennifer R. Rider,et al.  The TMPRSS2:ERG Rearrangement, ERG Expression, and Prostate Cancer Outcomes: A Cohort Study and Meta-analysis , 2012, Cancer Epidemiology, Biomarkers & Prevention.

[8]  B. Donnelly,et al.  ERG protein expression reflects hormonal treatment response and is associated with Gleason score and prostate cancer specific mortality. , 2012, European journal of cancer.

[9]  Isabell A. Sesterhenn,et al.  Clinical potential of the ERG oncoprotein in prostate cancer , 2012, Nature Reviews Urology.

[10]  A. Jemal,et al.  Cancer statistics, 2012 , 2012, CA: a cancer journal for clinicians.

[11]  T. H. van der Kwast,et al.  NKX3.1 Haploinsufficiency Is Prognostic for Prostate Cancer Relapse following Surgery or Image-Guided Radiotherapy , 2011, Clinical Cancer Research.

[12]  Alvaro A. Martinez,et al.  TMPRSS2/ERG fusion gene expression alters chemo‐ and radio‐responsiveness in cell culture models of androgen independent prostate cancer , 2011, The Prostate.

[13]  Arul M Chinnaiyan,et al.  Common gene rearrangements in prostate cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  H. Schlüter,et al.  ERG Status Is Unrelated to PSA Recurrence in Radically Operated Prostate Cancer in the Absence of Antihormonal Therapy , 2011, Clinical Cancer Research.

[15]  T. Tsuzuki,et al.  ERG gene rearrangement status in prostate cancer detected by immunohistochemistry , 2011, Virchows Archiv.

[16]  Wei Yan,et al.  Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. , 2011, Cancer cell.

[17]  Asha A. Nair,et al.  The ability of biomarkers to predict systemic progression in men with high-risk prostate cancer treated surgically is dependent on ERG status. , 2010, Cancer research.

[18]  R. Bristow,et al.  DNA repair targeting and radiotherapy: a focus on the therapeutic ratio. , 2010, Seminars in radiation oncology.

[19]  R. Bristow,et al.  Array CGH as a potential predictor of radiocurability in intermediate risk prostate cancer , 2010, Acta oncologica.

[20]  O. Kallioniemi,et al.  FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells. , 2010, Cancer research.

[21]  C. Sander,et al.  Integrative genomic profiling of human prostate cancer. , 2010, Cancer cell.

[22]  Martin J. Aryee,et al.  Androgen-induced TOP2B mediated double strand breaks and prostate cancer gene rearrangements , 2010, Nature Genetics.

[23]  S. Varambally,et al.  Antibody-based detection of ERG rearrangement-positive prostate cancer. , 2010, Neoplasia.

[24]  A. D'Amico,et al.  NCCN clinical practice guidelines in oncology: prostate cancer. , 2010, Journal of the National Comprehensive Cancer Network : JNCCN.

[25]  S. Varambally,et al.  Induced Chromosomal Proximity and Gene Fusions in Prostate Cancer , 2009, Science.

[26]  M. Dowsett,et al.  Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  M. Teitell,et al.  ETS family transcription factors collaborate with alternative signaling pathways to induce carcinoma from adult murine prostate cells , 2009, Proceedings of the National Academy of Sciences.

[28]  D. Dearnaley,et al.  Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. , 2009, Cancer research.

[29]  W. Gerald,et al.  TMPRSS2-ERG gene fusion is not associated with outcome in patients treated by prostatectomy. , 2009, Cancer research.

[30]  Martin Schostak,et al.  Expression and prognostic relevance of annexin A3 in prostate cancer. , 2008, European urology.

[31]  O. Ludkovski,et al.  Absence of TMPRSS2:ERG fusions and PTEN losses in prostate cancer is associated with a favorable outcome , 2008, Modern Pathology.

[32]  S. Srivastava,et al.  TMPRSS2-ERG fusion, a common genomic alteration in prostate cancer activates C-MYC and abrogates prostate epithelial differentiation , 2008, Oncogene.

[33]  C. D. Savci-Heijink,et al.  Gene panel model predictive of outcome in men at high-risk of systemic progression and death from prostate cancer after radical retropubic prostatectomy. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  J. Cuzick,et al.  Heterogeneity and clinical significance of ETV1 translocations in human prostate cancer , 2008, British Journal of Cancer.

[35]  A. Chinnaiyan,et al.  Recurrent gene fusions in prostate cancer , 2008, Nature Reviews Cancer.

[36]  J. Trachtenberg,et al.  Expression of the TMPRSS2:ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer , 2007, British Journal of Cancer.

[37]  Adam S. Kibel,et al.  TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort , 2007 .

[38]  Paul Schellhammer,et al.  Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. , 2006, International journal of radiation oncology, biology, physics.

[39]  A. Evans,et al.  Three-color FISH analysis of TMPRSS2/ERG fusions in prostate cancer indicates that genomic microdeletion of chromosome 21 is associated with rearrangement. , 2006, Neoplasia.

[40]  J. Tchinda,et al.  Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. , 2006, Science.

[41]  R. Bristow,et al.  Optimal treatment of intermediate‐risk prostate carcinoma with radiotherapy , 2005, Cancer.

[42]  W. Sauerbrei,et al.  Reporting recommendations for tumor marker prognostic studies (REMARK). , 2005, Journal of the National Cancer Institute.

[43]  D. Dearnaley,et al.  Construction of tissue microarrays from prostate needle biopsy specimens , 2005, British Journal of Cancer.

[44]  D. Eisenberg,et al.  Heterogeneity of molecular targets on clonal cancer lines derived from a novel hormone‐refractory prostate cancer tumor system , 2003, The Prostate.

[45]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[46]  G. Barendsen,et al.  Dose fractionation, dose rate and iso-effect relationships for normal tissue responses. , 1982, International journal of radiation oncology, biology, physics.

[47]  J. Fleiss.  Measuring nominal scale agreement among many raters. , 1971 .