<i>NKX3.1</i> Haploinsufficiency Is Prognostic for Prostate Cancer Relapse following Surgery or Image-Guided Radiotherapy

Locke, Jennifer A.; Zafarana, Gaetano; Ishkanian, Adrian; Milosevic, Michael; Thoms, John; Have, Cherry L.; Malloff, Chad A.; Lam, Wan L.; Squire, Jeremy A.; Pintilie, Melania; Sykes, Jenna; Ramnarine, Varune Rohan; Meng, Alice; Ahmed, Omer; Jurišica, Igor; Kwast, Theodorus H. van der; Bristow, Robert G.

doi:10.1158/1078-0432.ccr-11-2147

Cited by 41 publications

(38 citation statements)

References 32 publications

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“…) Given our goal to analyze IGRT patient outcome on the basis of aCGH or ERG overexpression as a prognostic versus predictive factor, we additionally determined whether fusion status was prognostic in a radical prostatectomy cohort in a similar low-to intermediate-risk cohort using a published dataset (37). Details for this surgical cohort were previously described (26). In this cohort, neither TMPRSS2-ERG fusion (by aCGH) nor ERG overexpression (based on mRNA abundance) were prognostic in 131 men with a median follow-up of 4.6 years (see Supplementary Figs.…”

Section: Resultsmentioning

confidence: 99%

“…25; Supplementary Table S1). The aCGH cohort consisted of 126 evaluable patients; further details on the assay technique and background tumor genetics for this cohort have been described previously (26). Clinical characteristics for both aCGH and IHC cohorts are presented in Table 1.…”

Section: Patient Cohorts and Treatment Deliverymentioning

confidence: 99%

“…The biopsy preparation, DNA extraction, aCGH procedure, and copy number detection were previously described (26,30). For each patient, the presence of a TMPRSS2-ERG gene fusion was defined as an observation of a 21q22.2-3 genomic deletion.…”

Section: Acgh Analysismentioning

confidence: 99%

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TMPRSS2-ERG Status Is Not Prognostic Following Prostate Cancer Radiotherapy: Implications for Fusion Status and DSB Repair

Pra

Lalonde

Sykes

et al. 2013

Clinical Cancer Research

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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 ERG overexpression (known surrogate for TMPRSS2-ERG fusion). Patients were treated with IGRT with 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 aCGH was 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.

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Section: Resultsmentioning

confidence: 99%

Section: Patient Cohorts and Treatment Deliverymentioning

confidence: 99%

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TMPRSS2-ERG Status Is Not Prognostic Following Prostate Cancer Radiotherapy: Implications for Fusion Status and DSB Repair

Pra

Lalonde

Sykes

et al. 2013

Clinical Cancer Research

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“…For clinical data, the primary outcome was biochemical relapse-free rate (bRFR) following the start of radiotherapy. Biochemical relapse was defined by the Phoenix criteria as a posttreatment PSA nadir plus 2 ng/mL or treatment of salvage hormones due to a rising PSA as previously described (19). Patients who did not experience a biochemical relapse by their last known PSA date were considered censored.…”

Section: Discussionmentioning

confidence: 99%

“…The clinical data are summarized in Supplementary Table S1, including the use of metformin or other oral hypoglycemic drugs (e.g., sulfonylureas, thiazolidinediones, meglitinide) and/or insulin. The total radiotherapy dose was escalated over the period of accrual in a series of separate phase I/II studies as previously published (19). The median radiation dose for the entire cohort was equivalent to 78 Gy in 2 Gy fractions.…”

Section: Patient Cohort and Treatment Characteristicsmentioning

confidence: 99%

Reprogramming Metabolism with Metformin Improves Tumor Oxygenation and Radiotherapy Response

Zannella

Pra

Muaddi

et al. 2013

Clinical Cancer Research

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Purpose: Tumor hypoxia is a negative prognostic factor in multiple cancers, due in part to its role in causing resistance to radiotherapy. Hypoxia arises in tumor regions distal to blood vessels as oxygen is consumed by more proximal tumor cells. Reducing the rate of oxygen consumption is therefore a potential strategy to reduce tumor hypoxia. We hypothesized that the anti-diabetic drug metformin, which reduces oxygen consumption through inhibition of mitochondrial complex I, would improve radiation response by increasing tumor oxygenation.Experimental Design: Tumor hypoxia was measured in xenografts before and after metformin treatment using 2-nitroimidazole hypoxia markers quantified by immunohistochemistry (IHC), flow cytometry, and positron emission tomography (PET) imaging. Radiation response was determined by tumor growth delay and clonogenic survival in xenografts with and without administration of metformin. The impact of metformin use on outcome was assessed in 504 patients with localized prostate cancer treated with curativeintent, image-guided radiotherapy (IGRT) from 1996 to 2012. Three-year biochemical relapse-free rates were assessed using the Kaplan-Meier method.Results: Metformin treatment significantly improved tumor oxygenation in two xenograft models as measured by IHC, flow cytometry, and PET imaging. Metformin also led to improved radiotherapy responses when mice were administered metformin immediately before irradiation. Clinically, metformin use was associated with an independent and significant decrease in early biochemical relapse rates (P ¼ 0.0106).Conclusion: Our data demonstrate that metformin can improve tumor oxygenation and response to radiotherapy. Our study suggests that metformin may represent an effective and inexpensive means to improve radiotherapy outcome with an optimal therapeutic ratio.

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Principles of Radiation Oncology

Connell,

Weichselbaum

2017

Holland‐Frei Cancer Medicine

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Overview In recent decades, we have witnessed major technologic advances that have influenced how radiotherapy is delivered to cancer patients. Simultaneously, our understanding of the underlying basic biology that governs radiation effects in human cells and tissues has grown rapidly. Here, we summarize some of these key advances and place them into the context of the evolving paradigms that shape cancer therapeutics more generally. Key biologic topics covered in this chapter involve the molecular responses of cells to DNA damage by ionizing radiation, including the repair of DNA damage, cell cycle arrest and death, cellular signaling, and the influence of tumor‐initiating cells (tumor stem cells) on post‐treatment outcomes. As radiation generates an inflammatory microenvironment in tumors, drugs that modulate immune functions also represent a potential therapeutic opportunity. We also describe newer biology‐based technologies that can accurately predict the intrinsic sensitivity of cells to radiation, and pharmacologic agents that can modulate this radiation sensitivity. Finally, this chapter reviews the major physics‐based technologic innovations that have improved the accuracy and utility of clinical radiotherapy. Despite these advances, several unmet challenges continue to limit the impact of radiotherapy, and these remaining hurdles should be the factors that guide future innovations of our field.

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NKX3.1 Haploinsufficiency Is Prognostic for Prostate Cancer Relapse following Surgery or Image-Guided Radiotherapy

Cited by 41 publications

References 32 publications

TMPRSS2-ERG Status Is Not Prognostic Following Prostate Cancer Radiotherapy: Implications for Fusion Status and DSB Repair

TMPRSS2-ERG Status Is Not Prognostic Following Prostate Cancer Radiotherapy: Implications for Fusion Status and DSB Repair

Reprogramming Metabolism with Metformin Improves Tumor Oxygenation and Radiotherapy Response

Principles of Radiation Oncology

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