Association of risk of clinical recurrence (CR) and prostate cancer death (PCD) with a 17-gene genomic prostate score (GPS) value <20.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5074-5074 ◽  
Author(s):  
Phillip G. Febbo ◽  
Michael Crager ◽  
Emily Burke ◽  
H. Jeffrey Lawrence ◽  
Jennifer Cullen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cox Regression ◽  
Intermediate Risk ◽  
Regression To The Mean ◽  
Sampling Weights ◽  
Clinical Recurrence ◽  
Hazard Ratios ◽  
Risk Prostate Cancer ◽  
Prostate Cancer Death

5074 Background: Over-treatment of localized prostate cancer (PC) can result from over-estimation of a patient’s risk of CR and PCD. GPS (scale 0-100) has been validated to predict adverse pathology, biochemical recurrence, metastasis, and PCD and provides a more accurate overall assessment of patient risk than clinical risk factors alone. A recent validation study found that no patients with AUA Low- or Intermediate-risk disease and a GPS of <20 developed PC metastases or PCD. Here, 2 large longitudinal PC cohorts were analyzed to estimate the risk of CR and PCD for GPS <or >20 units. Methods: Data from Klein et al. European Urology (EU) 2014 and Cullen et al. EU 2014 were analyzed to establish the risk of CR and PCD associated with a pre-established GPS cut-point of 20. Patients were divided based on the value of GPS (≤20, >20). Cox regression analyses accounted for cohort sampling weights. Since GPS was developed using Klein et al, standardized hazard ratios (std HR, HR for 1 SD change in the covariate) for GPS and CR and PCD survival curves for the 2 groups were estimated correcting for regression to the mean (RM). Results: Of the 402 patients in Cullen et al. (median follow up 5.2 years), only 5 patients developed metastases; all 5 had GPS >20. For Klein et al., of 426 patients with a median follow up of 6.6 years, there were 109 CR (metastasis and local recurrence) and 39 PCD; only one patient with events had a GPS <20. Overall 28% of patients had GPS <20. GPS was a significant predictor for both CR (std HR 2.50 (95%CI 1.99, 3.15, p <0.001, RM-corrected std HR 2.16, FDR <0.1%) and PCD (std HR 2.90 (95% CI 2.06,4.06, p<0.001, RM-corrected std HR 1.96, FDR <0.1%) after adjustment for AUA group. Men with intermediate risk prostate cancer and a GPS score of < 20 have a 2.6% and 0.7% 10-year RM-corrected risk of CR and PCD, respectively (Table 1). Conclusions: GPS strongly predicts risk of CR and PCD in men with AUA Low- or Intermediate-risk PC. Patients with a GPS score <20 have a very low risk of CR or PCD and should be considered for AS. [Table: see text]

scholarly journals Duration of Androgen Suppression Before Radiotherapy for Localized Prostate Cancer: Radiation Therapy Oncology Group Randomized Clinical Trial 9910

2015 ◽  
Vol 33 (4) ◽  
pp. 332-339 ◽  
Author(s):  
Thomas M. Pisansky ◽  
Daniel Hunt ◽  
Leonard G. Gomella ◽  
Mahul B. Amin ◽  
Alexander G. Balogh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Survival Rates ◽  
Intermediate Risk ◽  
Cancer Death ◽  
Disease Specific Survival ◽  
Risk Prostate Cancer ◽  
Prostate Cancer Death ◽  
Androgen Suppression ◽  
Disease Specific

Purpose To determine whether prolonged androgen suppression (AS) duration before radiotherapy improves survival and disease control in prostate cancer. Patients and Methods One thousand five hundred seventy-nine men with intermediate-risk prostate cancer were randomly assigned to 8 weeks of AS followed by radiotherapy with an additional 8 weeks of concurrent AS (16 weeks total) or to 28 weeks of AS followed by radiotherapy with an additional 8 weeks of AS (36 weeks total). The trial sought primarily to detect a 33% reduction in the hazard of prostate cancer death in the 28-week assignment. Time-to-event end points are reported for up to 10 years of follow-up. Results There were no between-group differences in baseline characteristics of 1,489 eligible patients with follow-up. For the 8- and 28-week assignments, 10-year disease-specific survival rates were 95% (95% CI, 93.3% to 97.0%) and 96% (95% CI, 94.6% to 98.0%; hazard ratio [HR], 0.81; P = .45), respectively, and 10-year overall survival rates were 66% (95% CI, 62.0% to 69.9%) and 67% (95% CI, 63.0% to 70.8%; HR, 0.95; P = .62), respectively. For the 8- and 28-week assignments, 10-year cumulative incidences of locoregional progression were 6% (95% CI, 4.3% to 8.0%) and 4% (95% CI, 2.5% to 5.7%; HR, 0.65; P = .07), respectively; 10-year distant metastasis cumulative incidences were 6% (95% CI, 4.0% to 7.7%) and 6% (95% CI, 4.0% to 7.6%; HR, 1.07; P = .80), respectively; and 10-year prostate-specific antigen–based recurrence cumulative incidences were 27% (95% CI, 23.1% to 29.8%) and 27% (95% CI, 23.4% to 30.3%; HR, 0.97; P = .77), respectively. Conclusion Extending AS duration from 8 weeks to 28 weeks before radiotherapy did not improve outcomes. A lower than expected prostate cancer death rate reduced ability to detect a between-group difference in disease-specific survival. The schedule of 8 weeks of AS before radiotherapy plus 8 weeks of AS during radiotherapy remains a standard of care in intermediate-risk prostate cancer.

scholarly journals Prostate-Specific Antigen Dynamics After Carbon Ion Radiotherapy for Prostate Cancer

2020 ◽  
Author(s):  
Yosuke Takakusagi ◽  
Takahiro Oike ◽  
Kio Kano ◽  
Wataru Anno ◽  
Keisuke Tsuchida ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prostate Specific Antigen ◽  
Specific Antigen ◽  
Carbon Ion Radiotherapy ◽  
Clinical Recurrence ◽  
Carbon Ion ◽  
Psa Bounce ◽  
Psa Failure ◽  
Risk Prostate Cancer

Abstract Background This study aimed to explain the dynamics of prostate-specific antigen (PSA) levels in patients with prostate cancer who were treated with carbon ion radiotherapy (CIRT) and neoadjuvant androgen-deprivation therapy (ADT). Methods Eighty-five patients with intermediate-risk prostate cancer who received CIRT and neoadjuvant ADT from December 2015 to December 2017 were analyzed in the present study. The total dose of CIRT was set at 51.6 Gy (relative biological effectiveness) delivered in 12 fractions over 3 weeks. The PSA bounce was defined as a ≥0.4 ng/ml increase of PSA levels from the nadir, followed by any decrease. PSA failure was defined using the Phoenix criteria.Results The median patient age was 68 (range, 48–81) years. The median follow-up duration was 33 (range, 20–48) months. The clinical T stage was T1c, T2a, and T2b in 26, 44, and 14 patients, respectively. The Gleason score was 6 in 3 patients and 7 in 82 patients. The median pretreatment PSA level was 7.37 (range, 3.33–19.0) ng/ml. All patients received neoadjuvant ADT for a median of 6 (range, 2–116) months. PSA bounces were observed in 39 patients (45.9%), occurring a median of 12 (range, 6–30) months after CIRT. PSA failure was observed in eight patients (9.4%), occurring a median of 21 (range, 15–33) months after CIRT. The 3-year PSA failure-free survival rate was 88.5%. No clinical recurrence was observed during the follow-up period. Younger age was a significant predictor of PSA bounces and PSA failure. Conclusions The dynamics of PSA levels after CIRT was investigated in the present study. Further follow-up is needed to reveal the clinical significance of PSA dynamics.

scholarly journals Observation with or without late radiotherapy is equivalent to early radiotherapy in high-risk prostate cancer after radical prostatectomy: A SEER-Medicare analysis on trends, survival outcomes and complications

2019 ◽  
Author(s):  
Young Suk Suk Kwon ◽  
Wei Wang ◽  
Arnav Srivast ◽  
Thomas L Jang ◽  
Singer A Eric ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Radical Prostatectomy ◽  
Cox Regression ◽  
Survival Outcomes ◽  
Study Cohort ◽  
High Risk Prostate Cancer ◽  
Pathologic Features ◽  
Risk Prostate Cancer

Abstract Introduction: While early radiotherapy (eRT) after radical prostatectomy (RP) has shown to improve oncologic outcomes in patients with high-risk prostate cancer (PCa) in a recent clinical trial, controversy remains regarding its benefit. We aimed to illustrate national trends of post-RP radiotherapy and compare outcomes and toxicities in patients receiving eRT vs. observation with or without late radiotherapy (lRT). Methods: Utilizing the Surveillance, Epidemiology and End Results (SEER)-Medicare data from 2001 to 2011, we identified 7557 patients with high-risk pathologic features after RP (≥ pT3N0 and/or positive surgical margins). Our study cohort was consisted of patients receiving RT within 6 months of surgery (eRT), those receiving RT after 6 months (IRT), and those never receiving RT (observation). Another subcohort, delayed RT (dRT), encompassed both IRT and observation. Trends of post-RP radiotherapy were compared using the Cochran-Armitage trend test. Cox regression models identified factors predictive of worse survival outcomes. Kaplan-Meier analyses compared the eRT and the dRT groups. Results: Among those with pathologically confirmed high-risk PCa after RP, 12.7% (n=959), 13.2% (n=1710), and 74.1% (n=4888) underwent eRT, lRT, and observation without RT, respectively. Of these strategies, the proportion of men on observation without RT increased significantly over time (p=0.004). Multivariable Cox regression model demonstrated similar outcomes between the eRT and the dRT groups. At a median follow up of 5.9 years, five-year overall and cancer-specific survival outcomes were more favorable in the dRT group, when compared to the eRT group. Radiation related toxicities, including urinary incontinence, erectile dysfunction, and urethral stricture, were higher in the eRT group when compared to the lRT group. Conclusions: Our results suggest that a blanket adoption of the eRT in high-risk PCa based on clinical trials with limited follow up may result in overtreatment of a significant number of men and expose them to unnecessary radiation toxicity.

Adverse pathology as a predictor of distant metastasis and prostate cancer mortality with 20-year follow up.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 219-219
Author(s):  
Michael Austin Brooks ◽  
Lewis Thomas ◽  
Cristina Magi-Galluzi ◽  
Jianbo Li ◽  
Michael Crager ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radical Prostatectomy ◽  
Active Surveillance ◽  
Distant Metastasis ◽  
Cancer Mortality ◽  
High Grade ◽  
Intermediate Risk ◽  
Sampling Weights ◽  
Prostate Cancer Mortality

219 Background: Adverse pathology (AP) at radical prostatectomy (RP) is often used as a proxy for long-term prostate cancer outcomes. The goal of this study was to assess the association of AP at RP, defined as high-grade (> Grade Group 3) and/or non-organ confined disease (pT3), with distant metastasis and prostate cancer death. Methods: A stratified cohort sample of 428 patients was used to evaluate the association of adverse pathology with the risk of distant metastases and prostate cancer-specific mortality over 20 years after prostatectomy in 2641 patients treated between 1987-2004. Cox regression of cause-specific hazards was used to estimate the absolute risk of both endpoints, with death from other causes treated as a competing risk. Subgroup analysis in patients with low/intermediate risk disease potentially eligible for active surveillance was performed. Results: Among the 428 patients, 343 had AUA Low or Intermediate risk disease and 85 had High risk disease. Median follow-up time was 15.5 years (IQR 14.6–16.6 years). Using the cohort sampling weights for estimation, at RP 29.8% of patients had high-grade disease, 42.3 % had non-organ confined disease, 19.3% had both, and thus 52.8% had AP. Adverse pathology was highly associated with metastasis and prostate cancer mortality in the overall cohort (HR 12.30, 95% CI 5.30-28.55, and 10.03, 95% CI 3.42-29.47, respectively, both p<0.001), and in the low/intermediate risk subgroup potentially eligible for active surveillance (HR 10.48, 95% CI 4.18-26.28, and 8.60, 95% CI 2.40-30.84, respectively, both p≤0.001). Conclusions: Adverse pathology at radical prostatectomy is highly associated with future development of metastasis and prostate cancer mortality and may be used as a short-term predictor of outcomes. [Table: see text]

Focal Cryotherapy for Clinically Unilateral, Low-Intermediate Risk Prostate Cancer in 73 Men with a Median Follow-Up of 3.7 Years

2012 ◽  
Vol 62 (1) ◽  
pp. 55-63 ◽  
Author(s):  
Duke Bahn ◽  
Andre Luis de Castro Abreu ◽  
Inderbir S. Gill ◽  
Andrew J. Hung ◽  
Paul Silverman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Intermediate Risk ◽  
Risk Prostate Cancer

Performance of MRI-TRUS-guided fusion biopsy to detect progression on active surveillance for low- and intermediate-risk prostate cancer.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 43-43
Author(s):  
Thomas P. Frye ◽  
Nabeel Ahmad Shakir ◽  
Steven Abboud ◽  
Arvin Koruthu George ◽  
Maria J Merino ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Active Surveillance ◽  
Low Risk ◽  
Intermediate Risk ◽  
Targeted Biopsy ◽  
Fusion Biopsy ◽  
Trus Biopsy ◽  
Guided Biopsy ◽  
Risk Prostate Cancer

43 Background: Active surveillance (AS) is an established treatment option for men with low risk prostate cancer. Its role in intermediate prostate cancer is still being investigated. Recent studies have shown that multiparametric-MRI (mp-MRI) along with MRI-TRUS fusion-guided biopsy may better assess risk in patients eligible for AS, compared to 12-core biopsy, due to improved detection of clinically significant cancers. The objective is to determine the performance of MRI-TRUS guided biopsy for men on AS with both low and intermediate risk disease. Methods: Between 2007-2014 men on AS were included if they had complete mp-MRI and pathology data for 2 or more MRI-TRUS biopsy sessions. Fusion guided biopsy procedures consisted of MRI identified targeted biopsies as well as random 12 core biopsies. Men were allowed to participate in AS with low and intermediate risk prostate cancer, Gleason score ≤ 3+4=7. Progression was defined by patients with initial Gleason 3+3=6 to any Gleason 4, and Gleason 3+4=7 disease progressing to a primary Gleason 4 or higher. Results: 89 men met our study criteria with an average age of 62 years old (range 45-79). 75 men had low risk Gleason 3+3=6 at the outset of AS by 1st biopsy session with a median PSA 5.1 ng/ml. The other 14 men had intermediate risk prostate cancer Gleason 3+4=7 at the outset of AS and a median PSA 4.6 ng/ml. During follow-up, 25 (33%) low risk men progressed to 3+4 or above at a median of 20.6 months. Of these, 19 were found by targeted biopsy. 6 (43%) of the intermediate risk men progressed to Gleason 4+3=7 at a median of 36.8 months. 4 of these progressed on targeted fusion biopsy. In the intermediate risk men, 84 random biopsy cores were require to detect 1 progression versus 15 targeted biopsy cores to detect 1 progression. Conclusions: The majority of patients on AS who progressed were identified by MRI-TRUS targeted biopsy. Less biopsy cores are required to detect progression with targeted biopsy. These results are preliminary and a larger cohort with longer follow-up would be beneficial.

Early toxicity in a prospective phase I/II trial of MRI-assisted focal boost integrated with HDR monotherapy for low- and intermediate-risk prostate cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 120-120
Author(s):  
Laura D'alimonte ◽  
Joelle Antoine Helou ◽  
Gerard Morton ◽  
Hans T. Chung ◽  
Merrylee McGuffin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase I ◽  
High Dose Rate ◽  
High Dose ◽  
Intermediate Risk ◽  
Hdr Brachytherapy ◽  
Gu Toxicity ◽  
Risk Prostate Cancer ◽  
Prospective Phase

120 Background: There is growing evidence for the use of High Dose Rate (HDR) brachytherapy as monotherapy for the treatment of low and intermediate risk prostate cancer patients. With the increasing availability of magnetic resonance imaging (MRI) there is an opportunity to further escalate dose to the dominant intraprostatic lesion (DIL). We report acute toxicity of this prospective phase I/II trial. Methods: Eligible patients had low- and intermediate risk prostate cancer, IPSS < 16, were medically eligible for HDR brachytherapy treatment and had an identified DIL on multiparametric MRI (mpMRI) prior to brachytherapy treatment. Patients were treated with 19 Gy delivered in one fraction to the whole prostate. A 0-5mm expansion was applied to the DIL to define the PTV DIL, with a DIL PTV D90 to receive > 23Gy based on previous experience. Toxicity was assessed using CTCAE v.4.0 at baseline, 6 weeks 3, 6, 9 and 12 months post brachytherapy. Results: A total of 34 patients have undergone HDR monotherapy treatment with an integrated DIL boost with a median follow up of 6 months. The median age was 67 years (range 46-80). At presentation, median PSA was 6.1 ng/mL (range 2.5-16.4). Three, 26, and 6 patients had low, low intermediate and high intermediate risk disease. Baseline characteristics were PIRAD 5 (n = 21) and PIRAD 4 (n = 13), median prostate volume was 38 cc (range 18-54). The median DIL volume was 2.8 cc (range 1.14-7.8). The median DIL D90 was 27 Gy (range 19-35.8). No patients experienced acute or late grade 2+ GI toxicity. The percentage of acute grade 2 GU toxicity were as follows; retention 62%, frequency 18%, urinary tract pain 6%. One patient had acute clot retention requiring catheterization x1 day and has been catheter-free since. Late grade 2 GU toxicity (alpha blockers) was reported in 6/16 patients at 6 months. Conclusions: The use of mpMRI to define and further escalate dose to the DIL using HDR monotherapy is feasible with minimal acute toxicities. Further long term follow up is required to determine the efficacy of treatment, and impact on quality of life and late toxicities. Clinical trial information: NCT02623933.

The relative contributions of the Genomic Prostate Score and comorbidity profile in predicting outcomes in surgically treated men with clinically low and intermediate-risk prostate cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16607-e16607
Author(s):  
Jennifer Cullen ◽  
Dudith Pierre-Victor ◽  
H. Jeffrey Lawrence ◽  
Huai-Ching Kuo ◽  
Isabell Sesterhenn ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Intermediate Risk ◽  
Free Survival ◽  
Risk Prostate Cancer ◽  
Risk Stratum ◽  
Diagnostic Biopsy ◽  
Using Data

e16607 Background: The 17-gene Oncotype Dx Genomic Prostate Score® (GPS™) assay has been validated as a predictor of aggressive prostate cancer (PCa) in men treated with radical prostatectomy (RP) for clinically low and intermediate risk PCa. This study examined the performance of the GPS assay as a predictor of adverse pathology (AP) and biochemical recurrence (BCR)-free survival (BRFS), after adjusting for the presence of major comorbidities commonly seen in older men. Methods: Additional analyses were performed using data from a prior clinical validation study of the GPS assay. GPS values (scaled 0-100), determined from diagnostic biopsy tissue, were categorized into 3 levels: lowest quartile (Q1), middle quartiles (combined Q2-Q3) versus the highest quartile (Q4). Major comorbidities included heart disease, stroke, COPD, and other cancers. The associations between GPS result and the presence of ≥1 major comorbidity and outcomes were examined. AP was defined as high-grade (Gleason Score ≥ 4+3) and/or pT3 tumor. BCR was defined as 2 successive PSA levels > 0.2 ng/mL. Logistic regression analysis was used to examine AP; Cox proportional hazards analysis was used to model BRFS. Results: Among 389 eligible men, median age at diagnosis and follow-up time was 62 and 5.6 years, respectively. The prevalence of ≥1 major comorbidity differed significantly across GPS category, rising from 10.2% to 19.7% to 25.5% for GPS Quartiles 1, 2-3, and 4, respectively (p = 0.0024). However, presence of ≥1 major comorbidity was not a significant predictor of AP or BCR in multivariable models with GPS, age, race, and NCCN risk stratum. Men whose GPS result was in the highest quartile had 4-fold higher odds of AP (OR: 4.1; 95% CI = 2.1-7.99, p < 0.0001) at RP and a 3.5 times higher risk of BCR (HR = 3.49; 95% CI = 1.59-7.64, p = 0.002) compared to men in the lowest GPS quartile (Table 1). Conclusions: A high GPS result remains the strongest predictor of BCR and AP in this cohort of low and intermediate risk PCa men, after adjusting for the presence of major comorbidities. Further work will explore the relationships between specific comorbidities and metabolic syndrome, with GPS testing and PCa outcomes.

scholarly journals Clinical Significance of Multiparametric Magnetic Resonance Imaging as a Preoperative Predictor of Oncologic Outcome in Very Low‐Risk Prostate Cancer

2019 ◽  
Vol 8 (4) ◽  
pp. 542
Author(s):  
Doo Yong Chung ◽  
Min Seok Kim ◽  
Jong Soo Lee ◽  
Hyeok Jun Goh ◽  
Dong Hoon Koh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radical Prostatectomy ◽  
Cox Regression ◽  
Low Risk ◽  
P Value ◽  
Resonance Imaging ◽  
Multiparametric Magnetic Resonance Imaging ◽  
Risk Prostate Cancer ◽  
Low Risk Prostate Cancer

Currently, multiparametric magnetic resonance imaging (mpMRI) is not an indication for patients with very low-risk prostate cancer. In this study, we aimed to evaluate the usefulness of mpMRI as a diagnostic tool in these patients. We retrospectively analyzed the clinical and pathological data of individuals with very low-risk prostate cancer, according to the NCCN guidelines, who underwent mpMRI before radical prostatectomy at our institution between 2010 and 2016. Patients who did not undergo pre-evaluation with mpMRI were excluded. We analyzed the factors associated with biochemical recurrence (BCR) using Cox regression model, logistic regression analysis, and Kaplan–Meier curve. Of 253 very low-risk prostate cancer patients, we observed 26 (10.3%) with BCR during the follow-up period in this study. The median follow-up from radical prostatectomy was 53 months (IQR 33–74). The multivariate Cox regression analyses demonstrated that the only factor associated with BCR in very low-risk patients was increase in the pathologic Gleason score (GS) (HR: 2.185, p-value 0.048). In addition, multivariate logistic analyses identified prostate specific antigen (PSA) (OR: 1.353, p-value 0.010), PSA density (OR: 1.160, p-value 0.013), and suspicious lesion on mpMRI (OR: 1.995, p-value 0.019) as the independent preoperative predictors associated with the pathologic GS upgrade. In our study, the pathologic GS upgrade after radical prostatectomy in very low-risk prostate cancer patients demonstrated a negative impact on BCR and mpMRI is a good prognostic tool to predict the pathologic GS upgrade. We believe that the implementation of mpMRI would be beneficial to determine the treatment strategy for these patients.

Using NBN to predict biochemical relapse following image-guided radiotherapy (IGRT) for intermediate-risk prostate cancer (IR-PCa).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 26-26
Author(s):  
Alejandro Berlin ◽  
Emilie Lalonde ◽  
Gaetano Zafarana ◽  
Jenna Sykes ◽  
Varune Rohan Ramnarine ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Copy Number ◽  
Prostate Cancer Cell ◽  
Local Treatment ◽  
Intermediate Risk ◽  
Biochemical Relapse ◽  
Image Guided Radiotherapy ◽  
Image Guided ◽  
Risk Prostate Cancer

26 Background: Despite the use of clinical prognostic factors, 20 to 40% of patients with intermediate-risk prostate cancer (IR-PCa) fail local treatment for unexplained reasons. Given that an accurate DNA damage response (DDR) may be associated with genetic instability and radioresponse, we investigated whether copy number alterations (CNAs) in DDR genes are predictive or prognostic following local treatment. Methods: Using array comparative genomic hybridization (aCGH), we characterized CNAs in biopsies derived from 126 IR-PCa pts. who underwent image-guided radiotherapy (IGRT). We studied the DDR-sensing genes: MRE11A, RAD50, NBN, ATM, and ATR. The IGRT cohort (median dose: 76.4Gy; median follow-up: 7.8yrs) was compared to a radical prostatectomy (RP) cohort (154 pts. from Memorial Sloan-Kettering Cancer Center database; median follow-up: 4.8yrs). CNAs were then tested for their independent prognostic capability using Kaplan-Meir method and Cox proportional hazard models. Results: In our IGRT cohort, m,ost frequent DDR gene CNAs were: NBN 20 of 126 (15.9%), ATR 11of 126 (8.7%), and ATM 7 of 126 (5.5%). NBN CNAs were mainly gains (19/20) and strongly correlated with increased NBN-mRNA abundance compared to NBN-neutral cases (p=0.016). CNAs in DDR genes were not associated with GS, prostate-specific antigen, or T-stage. Importantly, NBN gain ranked among the top 3.3% of all genes in terms of its strength of association with the percent of the genome altered (PGA). After adjusting for clinical factors in a multivariate model, NBN gain was a significant independent predictor of 5 years-biochemical relapse-free rate (bRFR) following IGRT (48.6% versus 78.8%; HR = 3.14, 95% CI: 1.42-6.94, p=0.004). No DDR CNA was prognostic in the RP cohort. Increased NBN mRNA expression correlated to radioresistance in vitro (i.e. clonogenic surviving fraction after 3Gy) in five prostate cancer cell lines (R2= 0.665). This relationship was not observed for any of the other DDR genes. Conclusions: NBN copy number gain or increased expression correlates with tumor genomic instability, decreased bRFR (IGRT- but not surgery-treated pts.) and intrinsic prostate cancer cell radioresistance. If validated in independent IGRT cohorts, NBN gain could be the first PCa predictive biomarker to facilitate local treatment decisions using precision medicine approaches.

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