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5005 Background: Risk stratification of prostate cancer (PC) using routine clinical variables remains suboptimal as they do not account for underlying tumor biology. The genomic classifier provides information on underlying biology and independently predicts an individual patient’s risk of metastasis. Although the performance of the genomic classifier has been tested across different cohorts primarily comprised of White men, its validation as an optimal genomic risk classifier for African American men (AAM) is thus far lacking in a prospective trial. We report the initial results on the prospective validation of the genomic classifier in a matched cohort of AAM and non-AAM (NAAM). Methods: This was a multisite, prospective validation trial of the genomic classifier i.e. Decipher score in AAM. Participants were recruited on a 1:1 enrollment ratio of AAM to NAAM diagnosed with low-intermediate risk PC. Patient on active surveillance were ineligible. NAAM were matched to AAM on PSA, age, biopsy Gleason score, clinical stage, and percent positive biopsy cores. Diagnostic biopsy specimens were processed at a CLIA certified laboratory and Decipher score was assessed using whole transcriptome profiling platform. Total target accrual was 250 men treated for low-intermediate PC over three years. Statistical analyses include categorical comparison of race dependent risk group migration between NCCN risk group and genomic classifier. Relative risk of metastasis was estimated using negative binomial model. Results: Final analytical cohort included 207 evaluable cases (AAM = 102 and NAAM = 107) with comprehensive genomic information. Risk of metastasis was determined based on pretreatment biopsy Decipher score, and patients were classified as low, favorable-, and unfavorable intermediate risk. Despite achieving a robustly matched clinical cohort, we observed significant genomic heterogeneity between AAM and NAAM across NCCN risk groups. In a comparative analysis, 49% of low-favorable intermediate risk AAM harbored high genomic risk tumors as compared to only 10% NAAM, p = 0.02. Similarly, using the modified clinico-genomic risk classifier (cGC), comprised of both Decipher score and clinical variables, AAM experienced an extreme deviation of risk status (difference [δ] between cGC and NCCN ≥ 2) as compared to NAAM (26.8% vs 8.1%, p = 0.03). In a binomial model, low-favorable NCCN risk AAM were 3.9 times more likely to be reclassified as high genomic risk for distant metastasis compared to NAAM (RR = 3.99, 95% CI, 1.15 – 13.86, p = 0.02). Conclusions: Clinical NCCN risk classification is an inadequate surrogate of tumor biology and offers suboptimal risk stratification for AAM with PC. Integration of patient specific genomic classifier into standard of care will improve accuracy in disease risk classification and treatment recommendations for AAM. Clinical trial information: NCT02723734.

To describe long-term outcomes and toxicity after salvage brachytherapy (BT) for local failure after initial radiotherapy for prostate cancer.Between 1994 and 2008, 37 men with local failure after initial prostate radiotherapy (32 external-beam radiation therapy [EBRT] and 5 BT) underwent salvage BT with (103)Pd or (125)I. Estimates of freedom from biochemical failure (FFbF, Phoenix definition) and cause-specific survival (CSS) were calculated using the Kaplan-Meier method. Toxicities were graded using CTCv3.0.Median follow-up was 86 months (range, 2-156). The median dose to 90% of the prostate volume was 122 Gy (range, 67-166). The 10-year FFbF and CSS were 54% and 96%, respectively. On univariate analysis, prostate-specific antigen (PSA)10 ng/mL at initial diagnosis was significantly associated with FFbF (p = 0.01), and there were trends for both age70 years (p = 0.08) and PSA6 ng/mL (p = 0.08) at the time of salvage BT. On multivariate analysis, only presalvage PSA6 ng/mL (p = 0.046) was significantly associated with improved FFbF. There were three Grade 3 toxicities and one Grade 4 toxicity. Pelvic lymph node dissection before salvage BT was the only variable significantly associated with Gradeor = 2 toxicity (p = 0.03).With a median follow-up of 86 months, salvage prostate BT was associated with a 10-year FFbF of 54% and CSS of 96%. Improved FFbF was associated with a presalvage PSA6 ng/mL. Toxicity was worse in patients who had undergone pelvic lymph node dissection before salvage BT. Careful patient selection for salvage BT may result in improved outcomes and reduced toxicity.

To evaluate the influence of patient- and treatment-related factors on freedom from biochemical failure (FFbF) in patients with intermediate-risk prostate cancer.From a prospectively collected database of 2250 men treated at Mount Sinai Hospital from 1990 to 2004 with low-dose-rate brachytherapy for prostate cancer, 558 men with either one or more intermediate-risk features (prostate-specific antigen [PSA] level 10-20 ng/mL, Gleason score 7, or Stage T2b) were identified who had a minimum follow-up of 24 months and postimplant CT-based dosimetric analysis. Biologically effective dose (BED) values were calculated to compare doses from different isotopes and treatment regimens. Patients were treated with brachytherapy with or without hormone therapy and/or external-beam radiotherapy. Patient- and treatment-related factors were analyzed with respect to FFbF. The median follow-up was 60 months (range, 24-167 months). Biochemical failure was defined according to the Phoenix definition. Univariate analyses were used to determine whether any variable was predictive of FFbF. A two-sided p value of0.05 was considered significant.Overall, the actuarial FFbF at 10 years was 86%. Dose (BED150 Gy(2) vs.or=150 Gy(2)) was the only significant predictor of FFbF (p0.001). None of the other variables (PSA, external-beam radiotherapy, Gleason score, treatment type, hormones, stage, and number of risk factors) was found to be a statistically significant predictor of 10-year FFbF.Radiation dose is an important predictor of FFbF in intermediate-risk prostate cancer. Treatment should continue to be individualized according to presenting disease characteristics until results from Radiation Therapy Oncology Group trial 0232 become available.

The objective of this study was to determine whether an association exists between certain single nucleotide polymorphisms (SNPs), which have previously been linked with adverse normal tissue effects resulting from radiotherapy, and the development of radiation injury resulting from radiotherapy for prostate cancer. A total of 135 consecutive patients with clinically localized prostate cancer and a minimum of 1 year of follow-up who had been treated with radiation therapy, either brachytherapy alone or in combination with external-beam radiotherapy, with or without hormone therapy, were genotyped for SNPs in SOD2, XRCC1 and XRCC3. Three common late tissue toxicities were investigated: late rectal bleeding, urinary morbidity, and erectile dysfunction. Patients with the XRCC1 rs25489 G/A (Arg280His) genotype were more likely to develop erectile dysfunction after irradiation than patients who had the G/G genotype (67% compared to 24%; P=0.048). In addition, patients who had the SOD2 rs4880 T/C (Val16Ala) genotype exhibited a significant increase in grade 2 late rectal bleeding compared to patients who had either the C/C or T/T genotype for this SNP (8% compared to 0%; P=0.02). Finally, patients with the combination of the SOD2 rs4880 C/T genotype and XRCC3 rs861539 T/C (Thr241Met) genotype experienced a significant increase in grade 2 late rectal bleeding compared to patients without this particular genotypic arrangement (14% compared to 1%; P=0.002). These results suggest that SNPs in the SOD2, XRCC1 and XRCC3 genes are associated with the development of late radiation injury in patients treated with radiation therapy for prostate adenocarcinoma.

Purpose Combined brachytherapy and external beam radiation therapy (EBRT) of the prostate and seminal vesicles (SVs) is evolving as a successful treatment option for high-risk prostate cancer. Dose–volume histogram (DVH) analysis of the SV was performed in patients with biopsy-positive SV who received implantation of the SV and prostate. Methods and materials Fifteen consecutive patients with high-risk features (prostate-specific antigen [PSA] ≥ 10 ng/mL, Gleason score ≥7, or clinical stage ≥T2b) and a positive SV biopsy were treated with a 103Pd implant of the prostate and SV followed by 45 Gy of EBRT. DVHs were generated for the prostate and total SV volume (SVT). In addition, the SV was divided into 3-mm-thick volumes identified as SV1, SV2, SV3, SV4, SV5, and SV6 starting from the junction of the prostate and SV and extending distally. Delivered dose was defined as the D90 (dose delivered to 90% of the organ on DVH). Results The median number of seeds implanted into the prostate and the SVT was 59 (41–94) and 9 (4–21), respectively. The median D90 values for the prostate, SVT, SV1, SV2, SV3, SV4, SV5, and SV6 were 103.2 (87.4–137.1), 46.2 (4.0–69.4), 76.0 (31.2–147), 63.4 (25.1–145.9), 49.7 (15.3–118), 27.4 (9.3–135.1), 14.2 (2.3–100.3), and 3.9 (0–61.5) Gy, respectively. Conclusions Implantation of the SV using a real-time intraoperative approach is technically feasible and results in higher doses to the SV than has been reported with implantation of the prostate alone. Although dose distribution in the SV can be variable and unpredictable, these doses, in combination with 45 Gy of EBRT, may be adequate to control disease spread in these organs.

To evaluate retrospectively the biochemical outcomes of young men treated with low-dose-rate brachytherapy for prostate cancer.From 1990 to 2005, 1,665 men with clinically localized prostate cancer were treated with low-dose-rate brachytherapy +/- hormone therapy (HT) +/- external beam radiotherapy and underwentor = 2 years of follow-up. Patients were stratified on the basis of age:or = 60 (n = 378) and60 years (n = 1,287). Biochemical failure was defined as a prostate-specific antigen (PSA) nadir plus 2 ng/mL. Univariate and multivariate analyses were used to determine the association of variables with freedom from biochemical failure (FFbF).Median follow-up was 68 months (range, 24-180) for menor = 60 years and 66 months (range, 24-200) for men60. For the entire group, the actuarial 5- and 8-year FFbF rates were 94% and 88%, respectively. Menor = 60 demonstrated similar 5- and 8-year FFbF (95% and 92%) compared with men60 (93% and 87%; p = 0.071). A larger percent of young patients presented with low-risk disease; lower clinical stage, Gleason score (GS), and pretreatment PSA values; were treated after 1997; did not receive any HT; and had a high biologic effective dose (BED) of radiation (all ps0.001). On multivariate analysis, PSA (p = 0.001), GS (p = 0.005), and BED (p0.001) were significantly associated with FFbF, but age was not (p = 0.665).Young men achieve excellent 5- and 8-year biochemical control rates that are comparable to those of older men after prostate brachytherapy. Young age should not be a deterrent when considering brachytherapy as a primary treatment option for clinically localized prostate cancer.

Purpose To investigate whether the presence of single nucleotide polymorphisms (SNPs) located within TGFB1 might be predictive for the development of adverse quality-of-life outcomes in prostate cancer patients treated with radiotherapy. Methods and Materials A total of 141 prostate cancer patients treated with radiotherapy were screened for SNPs in TGFB1 using DNA sequencing. Three quality-of-life outcomes were investigated: ( 1 ) prospective decline in erectile function, ( 2 ) urinary quality of life, and ( 3 ) rectal bleeding. Median follow-up was 51.3 months (range, 12–138 months; SD, 24.4 months). Results Those patients who possessed either the T/T genotype at position −509, the C/C genotype at position 869 (pro/pro, codon 10) or the G/C genotype at position 915 (arg/pro, codon 25) were significantly associated with the development of a decline in erectile function compared with those who did not have these genotypes: 56% (9 of 16) vs. 24% (11 of 45) ( p = 0.02). In addition, patients with the −509 T/T genotype had a significantly increased risk of developing late rectal bleeding compared with those who had either the C/T or C/C genotype at this position: 55% (6 of 11) vs. 26% (34 of 130) ( p = 0.05). Conclusions Possession of certain TGFB1 genotypes is associated with the development of both erectile dysfunction and late rectal bleeding in patients treated with radiotherapy for prostate cancer. Therefore, identification of patients harboring these genotypes may represent a means to predict which men are most likely to suffer from poor quality-of-life outcomes after radiotherapy for prostate cancer.

Purpose: To examine whether possession of genetic alterations in the ATM (ataxia telangiectasia) gene is associated with rectal bleeding in a dose-dependent and volume-dependent manner. Methods and Materials: One hundred eight prostate cancer patients who underwent brachytherapy using either an 125 I implant, a 103 Pd implant, or the combination of external beam radiotherapy with a 103 Pd implant and had a minimum of 1 year follow-up were screened for DNA sequence variations in the 62 coding exons of the ATM gene using denaturing high-performance liquid chromatography. Rectal dose was reported as the volume (in cubic centimeters) of rectum receiving the brachytherapy prescription dose. The two-sided Fisher exact test was used to compare differences in proportions. Results: A significant correlation between the presence of any ATM sequence alteration and Grade 1 to 2 proctitis was obtained when the radiation dose to rectal tissue was quantified. Rectal bleeding occurred in 4 of 13 patients (31%) with a variant versus 1 of 23 (4%) without a genetic alteration for patients who had 3 of rectal tissue receiving the implant prescription dose ( p = 0.05). Of patients in whom 0.7–1.4 cm 3 of the rectum received the implant prescription, 4 of 11 (36%) with an ATM alteration exhibited Grade 1 to 2 proctitis, whereas 1 of 21 (5%) without a variant ( p = 0.04) developed this radiation-induced late effect. Conclusions: The possession of genetic variants in the ATM gene is associated with the development of radiation-induced proctitis after prostate cancer radiotherapy for patients who receive the full prescription dose to either a low or a moderate volume of rectal tissue.

e15162 Background: The risk of secondary rectal malignancies (SRMs) is a significant concern following radiation therapy for prostate cancer patients. Modern prostate radiotherapy techniques include the use of intensity modulated radiation therapy (IMRT) and rectal balloons to decrease treatment related toxicity. These technologies may also lower the likelihood of radiation-induced SRMs. In this study, a novel biologically-based carcinogenesis model was used to quantify and to compare the predicted risks of SRMs in men treated with or without a rectal balloon in place using either standard 3-D conformal radiotherapy (3D-CRT) or IMRT radiotherapy. Methods: Treatment plans were developed for ten clinically localized prostate cancer patients using CT scans obtained both with and without a rectal balloon in place. Target and normal structures were contoured, and dose-volume histograms (DVHs) for these organs were determined with a planned 3D-CRT dose of 75.6 Gy or with a planned IMRT dose of 81 Gy. A biologically-based mathematical model of spontaneous and radiation-induced carcinogenesis was used to determine the excess absolute risk of SRMs for each plan. These risks were then compared to one another and to the baseline population. Results: Treatment with IMRT and a rectal balloon in place resulted in a significantly lower mean rectal wall dose in all patients compared with treatment with 3D-CRT without a rectal balloon. The average mean rectal wall dose with IMRT and a rectal balloon in place was 31.0 Gy versus 40.1 Gy with 3D-CRT without the rectal balloon (p < 0.001). A significantly higher risk of SRMs was predicted for patients treated with 3-D CRT without rectal balloons when compared with patients treated with IMRT with balloons in place (p < 0.001, relative risk 1.30; 95% confidence interval 1.16-1.44). Conclusions: For prostate cancer patients treated with definitive radiotherapy, the use of IMRT and rectal balloons during radiation, when compared to treatment with 3-D conformal radiotherapy, is associated with a significant reduction in the predicted risk of secondary rectal malignancies.