Karnes, R. Jeffrey

Objectives To determine if a re‐transurethral resection (TUR), in the presence or absence of muscle at the first TUR in patients with T1‐high grade (HG)/Grade 3 (G3) bladder cancer, makes a difference in recurrence, progression, cancer specific (CSS) and overall survival (OS). Patients and methods In a large retrospective multicentre cohort of 2451 patients with T1‐HG/G3 initially treated with bacille Calmette–Guérin, 935 (38%) had a re‐TUR. According to the presence or absence of muscle in the specimen of the primary TUR, patients were divided in four groups: group 1 (no muscle, no re‐TUR), group 2 (no muscle, re‐TUR), group 3 (muscle, no re‐TUR) and group 4 (muscle, re‐TUR). Clinical outcomes were compared across the four groups. Results Re‐TUR had a positive impact on recurrence, progression, CSS and OS only if muscle was not present in the primary TUR specimen. Adjusting for the most important prognostic factors, re‐TUR in the absence of muscle had a borderline significant effect on time to recurrence [hazard ratio (HR) 0.67, P = 0.08], progression (HR 0.46, P = 0.06), CSS (HR 0.31, P = 0.07) and OS (HR 0.48, P = 0.05). Re‐TUR in the presence of muscle in the primary TUR specimen did not improve the outcome for any of the endpoints. Conclusions Our retrospective analysis suggests that re‐TUR may not be necessary in patients with T1‐HG/G3, if muscle is present in the specimen of the primary TUR.

Abstract Purpose: Prostate cancers incite tremendous morbidity upon metastatic growth. We previously identified Asporin (ASPN) as a potential mediator of metastatic progression found within the tumor microenvironment. ASPN contains an aspartic acid (D)-repeat domain and germline polymorphisms in D-repeat-length have been associated with degenerative diseases. Associations of germline ASPN D polymorphisms with risk of prostate cancer progression to metastatic disease have not been assessed. Experimental Design: Germline ASPN D-repeat-length was retrospectively analyzed in 1,600 men who underwent radical prostatectomy for clinically localized prostate cancer and in 548 noncancer controls. Multivariable Cox proportional hazards models were used to test the associations of ASPN variations with risk of subsequent oncologic outcomes, including metastasis. Orthotopic xenografts were used to establish allele- and stroma-specific roles for ASPN D variants in metastatic prostate cancer. Results: Variation at the ASPN D locus was differentially associated with poorer oncologic outcomes. ASPN D14 [HR, 1.72; 95% confidence interval (CI), 1.05–2.81, P = 0.032] and heterozygosity for ASPN D13/14 (HR, 1.86; 95% CI, 1.03–3.35, P = 0.040) were significantly associated with metastatic recurrence, while homozygosity for the ASPN D13 variant was significantly associated with a reduced risk of metastatic recurrence (HR, 0.44; 95% CI, 0.21–0.94, P = 0.035) in multivariable analyses. Orthotopic xenografts established biologic roles for ASPN D14 and ASPN D13 variants in metastatic prostate cancer progression that were consistent with patient-based data. Conclusions: We observed associations between ASPN D variants and oncologic outcomes, including metastasis. Our data suggest that ASPN expressed in the tumor microenvironment is a heritable modulator of metastatic progression. Clin Cancer Res; 22(2); 448–58. ©2015 AACR.

Objective To evaluate the incidence, predictors and oncological outcomes of pT 0 prostate cancer ( PC a). Methods We conducted a retrospective analysis of 20 222 patients undergoing radical prostatectomy ( RP ) for PC a at the Mayo Clinic between 1987 and 2012. Disease recurrence was defined as follow‐up PSA >0.4 ng/mL or biopsy‐proven local recurrence. Systemic progression was defined as development of metastatic disease on imaging. Comparisons of baseline characteristics between pT 0 and non‐ pT 0 groups were carried out using chi‐squared tests. Recurrence‐free survival was estimated using the Kaplan–Meier method and compared using the log‐rank test. Results A total of 62 patients (0.3%) had pT 0 disease according to the RP specimen. In univariable analysis, pT 0 disease was significantly associated with older age ( P = 0.045), lower prostate‐specific antigen ( PSA ; P = 0.002), lower clinical stage ( P < 0.001), lower biopsy Gleason score ( P = 0.042), and receipt of preoperative transurethral resection, hormonal and radiation therapies (all P < 0.001). In multivariable analysis, lower PSA levels, lower Gleason score, and receipt of preoperative treatment were independently associated with pT 0 (all P < 0.05). Seven patients (11%) with pT 0 PC a developed disease recurrence over a median follow‐up of 10.9 years. All seven patients had preoperative treatment(s) and three had recurrence with a PSA doubling time of <9 months. Compared with non‐ pT 0 disease, pT 0 disease was associated with longer recurrence‐free survival ( P < 0.05). Only one (1.6%) patient with pT 0 disease developed systemic progression. Conclusions pT 0 stage PC a is a rare phenomenon and is associated with receipt of preoperative treatment and features of low‐risk PC a. Although pT 0 has a very favourable prognosis, some men, especially those who received preoperative treatment, experience a small but non‐negligible risk of disease recurrence and systemic progression.

Abstract Emerging evidence demonstrates that the DNA repair kinase DNA-PK exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PK functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PK inhibits tumor metastases. Clinical assessment revealed that DNA-PK is significantly elevated in advanced disease, and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PK in advanced tumors is highly activated, independently of DNA damage indicators. Combined, these findings put forth new paradigms for DNA-PK function, identify DNA-PK as a potent driver of tumor progression and metastases, and nominate DNA-PK as a therapeutic target for advanced malignancies. Citation Format: Jonathan F. Goodwin, Vishal Kothari, Justin M. Drake, Shuang Zhao, Emanuela Dylgjeri, Jeffry L. Dean, Matthew J. Schiewer, Christopher McNair, Michael S. Magee, Robert B. Den, Ziqi Zhu, Nicholas A. Graham, Ajay A. Vashisht, James A. Wohlschlegel, Thomas G. Graeber, R Jeffrey Karnes, Mandeep Takhar, Elai Davicioni, Scott A. Tomlins, Nima Sharifi, Owen N. Witte, Felix Y. Feng, Karen E. Knudsen. DNA-PK-mediated transcriptional regulation drives tumor progression and metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1860. doi:10.1158/1538-7445.AM2015-1860

Objectives To evaluate oncological outcomes after combination intravesical therapy with gemcitabine ( GC ) and mitomycin C ( MMC ) in the setting of recurrent non‐muscle‐invasive bladder cancer ( NMIBC ) after failure of previous intravesical therapy. Patients and Methods We retrospectively identified patients with recurrent NMIBC after previous intravesical therapy, who refused or were not candidates for cystectomy, between 2005 and 2011. GC and MMC were sequentially instilled weekly for 6–8 weeks. Data were collected regarding patient demographics, bladder cancer history, and number and type of intravesical therapies before GC / MMC . Outcomes evaluated included time to recurrence and/or progression after GC / MMC . Recurrence‐free outcomes were estimated using the Kaplan–Meier method, and Cox proportional hazards regression models were used to test the association of clinicopathological features with outcomes. Results In all, 27 patients were identified, 23 with high‐risk disease (high‐grade or carcinoma in situ ) and four with intermediate‐risk disease (multifocal or recurrent low‐grade). All patients received prior intravesical therapy, and 17 patients (63%) received multiple courses. Twenty‐four patients were treated with BCG . The median (range) disease‐free survival of all patients was 15.2 (1.7–39.3) months. Seventeen patients (63%) developed recurrent bladder cancer, a median of 15.2 months after therapy. One patient progressed to muscle‐invasive disease 5 months after treatment, and one developed metastatic disease 22 months after treatment. Three patients went on to cystectomy. Ten patients (37%) had no evidence of disease at last follow‐up, with a median follow‐up of 22.1 months. Conclusion The combination of intravesical GC and MMC could offer durable recurrence‐free survival to some patients with recurrent NMIBC who are not candidates for, or refuse, cystectomy.

Purpose The optimal timing of postoperative radiotherapy (RT) after radical prostatectomy (RP) is unclear. We hypothesized that a genomic classifier (GC) would provide prognostic and predictive insight into the development of clinical metastases in men receiving post-RP RT and inform decision making. Patients and Methods GC scores were calculated from 188 patients with pT3 or margin-positive prostate cancer, who received post-RP RT at Thomas Jefferson University and Mayo Clinic between 1990 and 2009. The primary end point was clinical metastasis. Prognostic accuracy of the models was tested using the concordance index for censored data and decision curve analysis. Cox regression analysis tested the relationship between GC and metastasis. Results The cumulative incidence of metastasis at 5 years after RT was 0%, 9%, and 29% for low, average, and high GC scores, respectively (P = .002). In multivariable analysis, GC and pre-RP prostate-specific antigen were independent predictors of metastasis (both P < .01). Within the low GC score (< 0.4), there were no differences in the cumulative incidence of metastasis comparing patients who received adjuvant or salvage RT (P = .79). However, for patients with higher GC scores (≥ 0.4), cumulative incidence of metastasis at 5 years was 6% for patients treated with adjuvant RT compared with 23% for patients treated with salvage RT (P < .01). Conclusion In patients treated with post-RP RT, GC is prognostic for the development of clinical metastasis beyond routine clinical and pathologic features. Although preliminary, patients with low GC scores are best treated with salvage RT, whereas those with high GC scores benefit from adjuvant therapy. These findings provide the first rational selection of timing for post-RP RT.

Objective To better characterize the genomics of patients with biochemical recurrence ( BCR ) who have metastatic disease progression in order to improve treatment decisions for prostate cancer. Methods The expression profiles of three clinical outcome groups after radical prostatectomy ( RP ) were compared: those with no evidence of disease ( NED ; n = 108); those with BCR (rise in prostate‐specific antigen [ PSA ] level without metastasis; n = 163); and those with metastasis ( n = 192). The patients were profiled using Human Exon 1.0 ST microarrays, and outcomes were supported by a median 18 years of follow‐up. A metastasis signature was defined and verified in an independent RP cohort to ensure the robustness of the signature. Furthermore, bioinformatics characterization of the signature was conducted to decipher its biology. Results Minimal gene expression differences were observed between adjuvant treatment‐naïve patients in the NED group and patients without metastasis in the BCR group. More than 95% of the differentially expressed genes (metastasis signature) were found in comparisons between primary tumours of metastasis patients and the two other outcome groups. The metastasis signature was validated in an independent cohort and was significantly associated with cell cycle genes, ubiquitin‐mediated proteolysis, DNA repair, androgen, G‐protein coupled and NOTCH signal transduction pathways. Conclusion This study shows that metastasis development after BCR is associated with a distinct transcriptional programme that can be detected in the primary tumour. Patients with NED and BCR have highly similar transcriptional profiles, suggesting that measurement of PSA on its own is a poor surrogate for lethal disease. Use of genomic testing in patients undergoing RP with an initial rise in PSA level may be useful to improve secondary therapy decision‐making.

Purpose The role of adjuvant radiotherapy (aRT) in treating patients with pN1 prostate cancer is controversial. We tested the hypothesis that the impact of aRT on cancer-specific mortality (CSM) in these individuals is related to tumor characteristics. Methods We evaluated 1,107 patients with pN1 prostate cancer treated with radical prostatectomy and anatomically extended pelvic lymph node dissection between 1988 and 2010 at two tertiary care centers. All patients received adjuvant hormonal therapy with or without aRT. Regression tree analysis stratified patients into risk groups on the basis of their tumor characteristics and the corresponding CSM rate. Cox regression analysis tested the relationship between aRT and CSM rate, as well as overall mortality (OM) rate in each risk group separately. Results Overall, 35% of patients received aRT. At multivariable analysis, aRT was associated with more favorable CSM rate (hazard ratio [HR], 0.37; P < .001). However, when patients were stratified into risk groups, only two groups of men benefited from aRT: (1) patients with positive lymph node (PLN) count ≤ 2, Gleason score 7 to 10, pT3b/pT4 stage, or positive surgical margins (HR, 0.30; P = .002); and (2) patients with PLN count of 3 to 4 (HR, 0.21; P = .02), regardless of other tumor characteristics. These results were confirmed when OM was examined as an end point. Conclusion The beneficial impact of aRT on survival in patients with pN1 prostate cancer is highly influenced by tumor characteristics. Men with low-volume nodal disease (≤ two PLNs) in the presence of intermediate- to high-grade, non–specimen-confined disease and those with intermediate-volume nodal disease (three to four PLNs) represent the ideal candidates for aRT after surgery.