Genomic Classifier Identifies Men With Adverse Pathology After Radical Prostatectomy Who Benefit From Adjuvant Radiation Therapy

Den, Robert B.; Yousefi, Kasra; Trabulsi, Edouard J.; Abdollah, Firas; Choeurng, Voleak; Feng, Felix Y.; Dicker, Adam P.; Lallas, Costas D.; Gomella, Leonard G.; Davicioni, Elai; Karnes, R. Jeffrey

doi:10.1200/jco.2014.59.0026

Cited by 186 publications

(123 citation statements)

References 46 publications

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“…Multivariable analysis revealed SRT (PSA X0.5 ng ml − 1 ) and no RT were associated with an approximate fivefold increased rates of metastasis when compared with ART or SRT administered in the setting of MRD (PSA 0.2-0.49 ng ml − 1 ). These findings are consistent with the approximate fourfold risk observed by Den et al 16 , when initiation of RT was dichotomized around a PSA threshold of 0.2 ng ml − 1 and support a beneficial effect of earlier application of secondary local treatment in attaining longer term oncological control as was observed in clinical trials. 29 There appeared to be minimal utility associated with SRT instituted at higher PSA levels (⩾0.5 ng ml − 1 ), supporting previous evidence that the window of curability following biochemical recurrence remains small, and that radiation therapy has maximal oncological benefit when delivered at low PSAs.…”

Section: Discussionsupporting

confidence: 80%

“…13,14 Decipher has been examined in multiple cohorts and post-prostatectomy settings and has been found to be an independent predictor of metastasis among men followed expectantly and those receiving postoperative ART and SRT. [15][16][17] CAPRA-S and Decipher have also been shown to potentially help in the selection of men for ART as opposed to SRT, but these studies have lacked an untreated postprostatectomy cohort and were subject to bias. Here, using a multi-institutional database, we evaluate the combination of clinico-pathological and genomic risk in the context of postoperative therapeutic choices including adjuvant and salvage therapy as well as expectant management of disease with adverse pathological features.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of Postoperative Radiation in a Prostatectomy Cohort Adjusted for Clinical and Genomic Risk

Den

Yousefi

Trock

et al. 2016

International Journal of Radiation Oncology*Biology*Physics

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BACKGROUND: To date, there have been no published trials examining the impact of salvage radiation therapy (SRT) in the post-operative setting for prostate cancer (PCa). We conducted a retrospective, comparative study of post-operative radiation following radical prostatectomy (RP) for men with pT3 disease or positive margins (adverse pathological features, APF). METHODS: 422 PCa men treated at four institutions with RP and having APF were analyzed with a primary end point of metastasis. Adjuvant radiation treatment (ART, n = 111), minimal residual disease (MRD) SRT (n = 70) and SRT (n = 83) were defined by PSA levels of o 0.2, 0.2-0.49 and ⩾ 0.5 ng ml − 1 , respectively, before radiation therapy (RT) initiation. Remaining 157 men who did not receive additional therapy before metastasis formed the no RT arm. Clinical-genomic risk was assessed by Cancer of the Prostate Risk Assessment Post-Surgical (CAPRA-S) and Decipher. Cox regression was used to evaluate the impact of treatment on outcome. RESULTS: During the study follow-up, 37 men developed metastasis with a median follow-up of 8 years. Both CAPRA-S and Decipher had independent predictive value on multivariable analysis for metastasis (P o0.05). Adjusting for clinical-genomic risk, SRT and no RT had hazard ratios of 4.31 (95% confidence interval, 1.20-15.47) and 5.42 (95% confidence interval, 1.59-18.44) for metastasis compared with ART, respectively. No significant difference was observed between MRD-SRT and ART (P = 0.28). Men with low-to-intermediate CAPRA-S and low Decipher value have a low rate of metastatic events regardless of treatment selection. In contrast, men with high CAPRA-S and Decipher benefit from ART, however the cumulative incidence of metastasis remains high. CONCLUSIONS: The decision as to the timing and need for additional local therapy following RP is nuanced and requires providers and patients to balance risks of morbidity with improved oncological outcomes. Post-RP treatment can be safely avoided for men who are low risk by clinical-genomic risk, whereas those at high risk should favor enrollment in clinical trials. Prostate Cancer and Prostatic Diseases INTRODUCTIONAggressive treatment approaches that have not yet been shown to improve overall survival are controversial within oncology, particularly in the management of men with prostate cancer (PCa). 1,2 Three randomized clinical trials in men with nonmetastatic PCa following surgical resection showed that treatment with adjuvant radiation therapy (ART) as compared with observation resulted in lower rates of biochemical recurrence, yet had conflicting impact on metastasis-free and overall survival. [3][4][5] Given the disparate findings, there has been an increase in utilization of salvage radiation therapy (SRT) 6 with concomitant decrease in ART, despite no randomized prospective trial evidence supporting this clinical decision. Although multiple randomized clinical trials are ongoing, 7,8 results are not expected for several years. Thus, patients and physicians are left with mu...

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Efficacy of Postoperative Radiation in a Prostatectomy Cohort Adjusted for Clinical and Genomic Risk

Den

Yousefi

Trock

et al. 2016

International Journal of Radiation Oncology*Biology*Physics

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“…15 Use of this expression array protocol also allows for evaluation of various combinations of PSRs, and thus permits one to simultaneously assess other expression marker panels and data sets, 10,16,17 as well as evaluate new ones. To explore the transcriptomic differences between prostate biopsy and matched RP samples, and evaluate the effects of heterogeneity, we compared transcriptomic data generated using Human Exon arrays obtained from 158 different prostate tissue samples from 33 patients seen at three different institutions.…”

mentioning

confidence: 99%

Application of a Clinical Whole-Transcriptome Assay for Staging and Prognosis of Prostate Cancer Diagnosed in Needle Core Biopsy Specimens

Knudsen

Kim

Erho

et al. 2016

The Journal of Molecular Diagnostics

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Molecular and genomic analysis of microscopic quantities of tumor from formalin-fixed, paraffin-embedded biopsy specimens has many unique challenges. Herein, we evaluated the feasibility of obtaining transcriptome-wide RNA expression to measure prognostic classifiers in diagnostic prostate needle core biopsy specimens. One-hundred fifty-eight samples from diagnostic needle core biopsy specimens (BX) and radical prostatectomies (RPs) were collected from 33 patients at three hospitals; each patient provided up to six tumor and benign samples. Genome-wide transcriptomic profiles were generated using Affymetrix Human Exon arrays for comparison of gene expression alterations and prognostic signatures between the BX and RP samples. A sufficient amount of RNA (>100 ng) was obtained from all RP specimens (n Z 77) and from 72 of 81 of BX specimens. Of transcriptomic features detected in RP, 95% were detectable in BX tissues and demonstrated a high correlation (r Z 0.96). Likewise, an expression signature pattern validated on RPs (Decipher prognostic test) showed correlation between BX and RP (r Z 0.70). Of matched BX and RP pairs, 25% showed discordant molecular subtypes. Genome-wide exon arrays yielded data of comparable quality from biopsy and RP tissues. The high concordance of tumor-associated gene expression changes between BX and RP samples provides evidence for the adequate performance of the assay platform with samples from prostate needle biopsy specimens with limited tumor volume. (J Mol Diagn 2016, 18: 395e406; http://dx

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“…For example, Den et alcompared a genome classifier score between salvage and adjuvant radiation patients and its ability to predict clinical metastasis development [6]. However, these assays have not been shown to predict the likelihood of responding specifically to salvage local radiation after prostatectomy as we are examining in this study.…”

Section: Discussionmentioning

confidence: 67%

Use of the cell cycle progression (CCP) score for predicting systemic disease and response to radiation of biochemical recurrence

Koch

Cho

Kaimakliotis

et al. 2016

CBM

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Abstract. BACKGROUND: Determining the optimal treatment for biochemical recurrence (BCR) after radical prostatectomy (RP) is challenging. OBJECTIVE: We evaluated the ability of CCP score (a prognostic RNA expression signature) to discriminate between systemic disease and local recurrence in patients with BCR after RP. METHODS: Sixty patients with BCR after RP were selected for analysis based on: 1) metastatic disease, 2) non-response to salvage external beam radiotherapy (EBRT), and 3) durable response to salvage EBRT. CCP scores were generated from the RNA expression of 46 genes. Logistic regression assessed the association between CCP score and patient group. RESULTS: Passing CCP scores were generated for 47 patients with complete clinical and pathologic data. CCP score predicted clinical status when comparing patients with metastatic disease or non-responders to salvage therapy to patients with durable response (p = 0.006). CCP score remained significantly predictive of clinical status after accounting for time to BCR, PSA level at BCR, and Gleason score (p = 0.0031). CONCLUSIONS: Elevated CCP score was associated with increased risk of systemic disease, indicating that CCP score may be useful in identifying patients with BCR who are most likely to benefit from salvage radiation therapy.

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Genomic Classifier Identifies Men With Adverse Pathology After Radical Prostatectomy Who Benefit From Adjuvant Radiation Therapy

Cited by 186 publications

References 46 publications

Efficacy of Postoperative Radiation in a Prostatectomy Cohort Adjusted for Clinical and Genomic Risk

Efficacy of Postoperative Radiation in a Prostatectomy Cohort Adjusted for Clinical and Genomic Risk

Application of a Clinical Whole-Transcriptome Assay for Staging and Prognosis of Prostate Cancer Diagnosed in Needle Core Biopsy Specimens

Use of the cell cycle progression (CCP) score for predicting systemic disease and response to radiation of biochemical recurrence

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