BRCA carrier status as an independent prognostic factor associated with earlier biochemical relapse in local prostate cancer.

1545 Background: Biochemical relapse after local treatment for prostate cancer (PCa) indicates recurrent disease and is associated with shorter survival. Germline BRCA mutations are associated with worse PCa outcomes. BRCA carriers are currently treated with the same protocols used for non-carriers. We analyzed biochemical-progression free survival (bPFS) after conventional treatment for localized PCa in a cohort of BRCA patients (pts). Methods: In this retrospective case-control study, each BRCA carrier (9 BRCA1 and 34 BRCA2) treated with radical prostatectomy (RP) or external beam radiotherapy (RT) was matched with 3 non-carriers (NC) by age at diagnosis (±5 yrs), TNM stage, Gleason score, presenting PSA, local treatment , androgen-deprivation therapy (ADT) and year of treatment (±3 yrs). All NC were screened for BRCA1 and BRCA2 mutations. Biochemical failure was reviewed according to ASTRO and NCCN criteria. The Kaplan-Meier method and a multivariate Cox regression model adjusted by matching factors were employed. Results: 172 pts were included. Median follow-up was 76 months (ms). Median age at diagnosis was 58 yrs (43-75). Tumour stages were I 11%, IIA 19%, IIB 28%, III 28%, IV 14%. 80 pts received RT (18 BRCA2, 5 BRCA1, 57NC) and 85% also received ADT (70% for ≥6 months). 92 pts underwent RP (16 BRCA2, 4 BRCA1 and 72 NC), and 9% of them received ADT (<6months). Overall, median bPFS was 71ms. For those treated with RT, median bPFS was 65ms in NC vs 39ms in BRCA carriers (p=0.023). bPFS was not affected by ADT duration. Median bPFS after RP was 65ms in BRCA carriers. No difference was observed in 3yrs-bPFS between BRCA carriers and NC (73% vs 76%). The adjusted MVA confirmed the independent prognostic value of tumour stage (p=0.004) and BRCA status (p=0.032) for bPFS. Among BRCA carriers, the risk was greater when the analysis was limited to BRCA2 pts (p=0.013, HR 2.1,.95%CI 1.2-3.7). Conclusions: Our results suggest that BRCA carriers with PCa have worse local disease control than NC when treated with RT, regardless of ADT duration. No differences in bPFS were observed in pts treated with RP after >6 yrs median follow-up. These results may have implications for tailoring clinical management for these patients.

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Effect of germ-line BRCA mutations in biochemical relapse and survival after treatment for localized prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.29 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 29-29 ◽

Cited By ~ 1

Author(s):

Elena Castro ◽

David Olmos ◽

Chee Leng Goh ◽

Ed Saunders ◽

Daniel Leongamornlert ◽

...

Keyword(s):

Prostate Cancer ◽

Cox Regression ◽

Germ Line ◽

External Beam Radiotherapy ◽

Local Treatment ◽

Age At Diagnosis ◽

Biochemical Relapse ◽

Brca Mutations ◽

Brca Carriers

29 Background: Biochemical relapse after local treatment for prostate cancer (PCa) indicates recurrent disease and is associated with shorter cause-specific survival (CSS). Germline BRCA mutations are associated with worse PrCa outcomes. In this study, we analyzed biochemical-progression free survival (bPFS) after conventional treatments for localized PCa in a cohort of BRCA patients from the UK. Currently, BRCA1/2 carriers are treated with the same protocols used for non-carriers. Methods: In this retrospective case-control study, each BRCA carrier (10 BRCA1 and 34 BRCA2) treated with radical prostatectomy (RP) or external beam radiotherapy (RT) was matched with 3 non-carriers (NC) by: age at diagnosis (±5 yrs), TNM stage, Gleason score, presenting PSA, local treatment (RT or RP), androgen-deprivation therapy (ADT) and year of treatment (±5yrs). All NC were screened for BRCA1 and BRCA2 mutations. Biochemical failure was reviewed according to ASTRO and NCCN criteria. The Kaplan-Meier method and a multivariate Cox regression model adjusted by matching factors were employed. Results: 176 patients (pts) were included. Median follow-up was 97 months (ms). Median age at diagnosis was 58.5 yrs (43-75). 80 pts received RT (16 BRCA2, 4 BRCA1, 60 NC) and 85% also received ADT≥6 ms. 96pts underwent RP (18 BRCA2, 6 BRCA1 and 72 NC). Following RT treatment, 5yrs-CSS was 96% in NC and 47% in BRCA carriers (p=2x10-5), whilst no difference was seen after RP (5yrs-CSS was 98.5% in NC vs 93.3% in BRCA). Five-years bFPFS after RT was 74% in NC and 24% in BRCA (p=0.002). No difference was observed in 5yrs-bPFS between BRCA carriers and NC treated with RP (52% vs 66% , p=0.346). The adjusted MVA (including tumour stage, local treatment, ADT and BRCA status) confirmed the independent prognostic value of BRCA status for bPFS and CSS. Among BRCA carriers, the independent risk was greater when the analysis was limited to BRCA2 pts . Conclusions: Our results suggest that BRCA carriers have worse local disease control than NC when conventionally treated with RT. No differences in bPFS were observed in pts treated with RP after >8 yrs median follow-up. These results may have implications for tailoring clinical management in these patients.

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Adjuvant versus early salvage radiotherapy: outcome of patients with prostate cancer treated with postoperative radiotherapy after radical prostatectomy

Radiation Oncology ◽

10.1186/s13014-019-1391-0 ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 1

Author(s):

Marco M. E. Vogel ◽

Kerstin A. Kessel ◽

Kilian Schiller ◽

Michal Devecka ◽

Jürgen E. Gschwend ◽

...

Keyword(s):

Prostate Cancer ◽

Cox Regression ◽

Postoperative Radiotherapy ◽

Locally Advanced ◽

Local Treatment ◽

Salvage Radiotherapy ◽

Individual Treatment ◽

Biochemical Relapse ◽

Significant Difference

Abstract Background Adjuvant (ART) and salvage radiotherapy (SRT) are two common concepts to enhance biochemical relapse free survival (BCRFS) in patients with prostate cancer (PC). We analyzed differences in outcome between ART and SRT in patients with steep decline of PSA-levels after surgery to compare outcome. Methods We evaluated 253 patients treated with postoperative RT with a median age of 66 years (range 42–85 years) treated between 2004 and 2014. Patients with additive radiotherapy due to PSA persistence and patients in the SRT group, who did not achieve a postoperative PSA level <0.1 ng/mL were excluded. Hence, data of 179 patients was evaluated. We used propensity score matching to build homogenous groups. A Cox regression model was used to determine differences between treatment options. Median follow-up was 32.5 months (range 1.4–128.0 months). Results Early SRT at PSA levels <0.3 ng/mL was associated with significant longer BCRFS than late SRT (HR: 0.32, 95%-CI: 0.14–0.75, p = 0.009). Multiple Cox regression showed pre-RT PSA level, tumor stage, and Gleason score as predictive factors for biochemical relapse. In the overall group, patients treated with either ART or early SRT showed no significant difference in BCRFS (HR: 0.17, 95%-CI: 0.02–1.44, p = 0.1). In patients with locally advanced PC (pT3/4) BCRFS was similar in both groups as well (HR: 0.21, 95%-CI:0.02–1.79, p = 0.15). Conclusion For patients with PSA-triggered follow-up, close observation is essential and early initiation of local treatment at low PSA levels (<0.3 ng/mL) is beneficial. Our data suggest, that SRT administered at early PSA rise might be equieffective to postoperative ART in patients with locally advanced PC. However, the individual treatment decision must be based on any adverse risk factors and the patients’ postoperative clinical condition. Study registration The present work is approved by the Ethics Commission of the Technical University of Munich (TUM) and is registered with the project number 320/14.

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

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.26 ◽

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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Prostate Cancer: Transrectal High-Intensity Focused Ultrasound for the Treatment of Local Recurrence after Radical Prostatectomy or Radiotherapy

Urologia Journal ◽

10.1177/039156030907600204 ◽

2009 ◽

Vol 76 (2) ◽

pp. 73-76 ◽

Cited By ~ 1

Author(s):

M. Tasso ◽

F. Varvello ◽

U. Ferrando

Keyword(s):

Prostate Cancer ◽

Radical Prostatectomy ◽

Local Recurrence ◽

Focused Ultrasound ◽

External Beam Radiotherapy ◽

High Intensity Focused Ultrasound ◽

Biochemical Relapse ◽

Vesicourethral Anastomosis ◽

Disease Free

Objectives To evaluate the efficacy and safety of transrectal high-intensity focused ultrasound (HIFU) as salvage therapy for locally recurrent prostate cancer after external beam radiotherapy or recurrences located in the region of vesicourethral anastomosis after radical prostatectomy. Methods Transrectal biopsy of the prostate (recurrence after radiotherapy) or in the region of vesicourethral anastomosis (recurrence after prostatectomy) was performed in all cases at the time of biochemical relapse. Only patients with positive biopsy were treated. Systemic disease was excluded by PET-CT and bone scan. All treatments were carried out under spinal anesthesia. The device used was Ablatherm (EDAP, Lion, France). The patients were followed with PSA measurement every 3 months and clinical examination every 6 months. In case of biochemical relapse we performed re-biopsy. Results From 2002 to 2008 we treated 19 patients with local recurrence after radiotherapy. The mean follow-up was 30 months for each patient (range 6–72 months). 9 patients (47%) are disease-free at last follow-up, with PSA < 1 ng/mL. 9 patients experienced biochemical failure: 8 were treated with androgen deprivation, 1 with salvage prostatectomy. 2 patients died of the disease. Adverse events related to HIFU included 1 rectourethral fistula (observed before the use of specific parameters dedicated to this patient population) and mild incontinence (2–3 pads/die) in 4 patients. From 2002 to 2008 we treated 27 patients with a local recurrence after radical prostatectomy. Mean pre-HIFU PSA was 2.17 ng/mL (range 0.5–8 ng/ml); the Gleason score ranged from 5 to 8. All patients reached a minimum follow-up of 20 months (range 20–80 months). Median PSA nadir was 0.2 ng/ml. The disease-free rate was 51% (14/27); these patients have a median PSA of 0.2 ng/ml at last follow-up. 81% (22/27) of control biopsies were negative. There were no intra-operative or post-operative complications. Conclusions The small number of patients in our series limits our ability to draw any definitive conclusions. We believe that HIFU may be a potentially useful treatment option for patients who develop prostate cancer recurrence after external beam radiotherapy or in the region of vesicourethral anastomosis after radical prostatectomy. The procedure is safe, side effects are acceptable and do not add significant morbidity to the previous radical treatment. HIFU lesions are targeted only to the area of recurrence. It is important to remember that, in case of failure, the patient can undertake any other therapies.

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Comparison of the Efficacy of Local Therapies for Localized Prostate Cancer in the Prostate-Specific Antigen Era: A Large Single-Institution Experience With Radical Prostatectomy and External-Beam Radiotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2002.01.150 ◽

2002 ◽

Vol 20 (16) ◽

pp. 3376-3385 ◽

Cited By ~ 180

Author(s):

Patrick A. Kupelian ◽

Mohamed Elshaikh ◽

Chandana A. Reddy ◽

Craig Zippe ◽

Eric A. Klein

Keyword(s):

Prostate Cancer ◽

Radical Prostatectomy ◽

Treatment Modality ◽

External Beam Radiotherapy ◽

Specific Antigen ◽

Biochemical Failure ◽

External Beam ◽

Biochemical Relapse ◽

Definition Of

PURPOSE: To review biochemical relapse-free survival (bRFS) rates after either external-beam radiotherapy (RT) or radical prostatectomy (RP) for localized prostate cancer. PATIENTS AND METHODS: All 1,682 patients had pretreatment prostate-specific antigen (PSA) levels and biopsy Gleason scores (bGS) assigned. No adjuvant therapy was administered after local treatment. RP was the treatment in 1,054 patients (63%) and RT in 628 patients (37%). Median follow-up was 51 months (range, 1 to 134). The median follow-up for RP versus RT patients was 50.5 v 51.0 months. Biochemical relapse was considered detectable PSA levels (> 0.2 ng/mL) in RP patients and three consecutive rising PSA levels in RT patients. The analysis was repeated with a more stringent definition of biochemical control after either RP or RT—namely, reaching and maintaining a PSA level ≤ 0.5 ng/mL—and excluding patients receiving any androgen deprivation (AD). RESULTS: Eight-year bRFS rates for RP versus RT were 72% and 70%, respectively (P = .010). Multivariate analysis indicated T stage (P < .001), pretreatment PSA (P < .001), bGS (P < .001), year of therapy (P < .001), and neoadjuvant AD (P = .019) to be the only independent predictors of relapse. Age (P = .78), race (P = .29), prior transurethral resection of prostate (P = .81), and treatment modality (P = .96) were not independent predictors of treatment failure. Fifty-one percent of RP patients had favorable tumors (T1 to T2A, pretreatment PSA ≤ 10 ng/mL, bGS ≤ 7), compared with only 34% of RT patients (P < .001). Repeat analysis with a stringent definition of biochemical failure and excluding patients receiving AD indicated no impact of treatment modality on outcome. CONCLUSION: Eight-year biochemical failure rates were identical between RT and RP in any subgroup. Outcome is determined mainly by pretreatment PSA levels, bGS, clinical T stage, and, for RT patients, radiation dose.

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A novel predictor of clinical progression in patients on active surveillance for prostate cancer

Canadian Urological Association Journal ◽

10.5489/cuaj.6122 ◽

2019 ◽

Vol 13 (8) ◽

Author(s):

Guan Hee Tan ◽

Antonio Finelli ◽

Ardalan Ahmad ◽

Marian Wettstein ◽

Alexandre Zlotta ◽

...

Keyword(s):

Prostate Cancer ◽

Active Surveillance ◽

Cox Regression ◽

Area Under The Curve ◽

Progression Free Survival ◽

Roc Curves ◽

Standard Of Care ◽

Low Risk ◽

Clinical Progression

Introduction: Active surveillance (AS) is standard of care in low-risk prostate cancer (PC). This study describes a novel total cancer location (TCLo) density metric and aims to determine its performance in predicting clinical progression (CP) and grade progression (GP). Methods: This was a retrospective study of patients on AS after confirmatory biopsy (CBx). We excluded patients with Gleason ≥7 at CBx and <2 years follow-up. TCLo was the number of locations with positive cores at diagnosis (DBx) and CBx. TCLo density was TCLo / prostate volume (PV). CP was progression to any active treatment while GP occurred if Gleason ≥7 was identified on repeat biopsy or surgical pathology. Independent predictors of time to CP or GP were estimated with Cox regression. Kaplan-Meier analysis compared progression-free survival curves between TCLo density groups. Test characteristics of TCLo were explored with receiver operating characteristic (ROC) curves. Results: We included 181 patients who had CBx between 2012-2015, and met inclusion criteria. The mean age of patients was 62.58 years (SD=7.13) and median follow-up was 60.9 months (IQR=23.4). A high TCLo density score (>0.05) was independently associated with time to CP (HR 4.70, 95% CI: 2.62-8.42, p<0.001), and GP (HR 3.85, 95% CI: 1.91-7.73, p<0.001). ROC curves showed TCLo density has greater area under the curve than number of positive cores at CBx in predicting progression. Conclusion: TCLo density is able to stratify patients on AS for risk of CP and GP. With further validation, it could be added to the decision-making algorithm in AS for low-risk localized PC.

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Cognitive dispersion and ApoEe4 genotype predict dementia diagnosis in 8-year follow-up of the oldest-old

Age and Ageing ◽

10.1093/ageing/afaa232 ◽

2020 ◽

Author(s):

Tam Watermeyer ◽

Jantje Goerdten ◽

Boo Johansson ◽

Graciela Muniz-Terrera

Keyword(s):

Cognitive Performance ◽

Cox Regression ◽

Oldest Old ◽

Cost Effective ◽

Carrier Status ◽

Dementia Diagnosis ◽

Cognitive Domains ◽

Dementia Incidence ◽

Composite Scores

Abstract Background Cognitive dispersion, or inconsistencies in performance across cognitive domains, has been posited as a cost-effective tool to predict conversion to dementia in older adults. However, there is a dearth of studies exploring cognitive dispersion in the oldest-old (>80 years) and its relationship to dementia incidence. Objective The main aim of this study was to examine whether higher cognitive dispersion at baseline was associated with dementia incidence within an 8-year follow-up of very old adults, while controlling for established risk factors and suggested protective factors for dementia. Methods Participants (n = 468) were from the Origins of Variance in the Old-Old: Octogenarian Twins study, based on the Swedish Twin Registry. Cox regression analyses were performed to assess the association between baseline cognitive dispersion scores and dementia incidence, while controlling for sociodemographic variables, ApoEe4 carrier status, co-morbidities, zygosity and lifestyle engagement scores. An additional model included a composite of average cognitive performance. Results Cognitive dispersion and ApoEe4 were significantly associated with dementia diagnosis. These variables remained statistically significant when global cognitive performance was entered into the model. Likelihood ratio tests revealed that cognitive dispersion and cognitive composite scores entered together in the same model was superior to either predictor alone in the full model. Conclusions The study underscores the usefulness of cognitive dispersion metrics for dementia prediction in the oldest-old and highlights the influence of ApoEe4 on cognition in very late age. Our findings concur with others suggesting that health and lifestyle factors pose little impact upon cognition in very advanced age.

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