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563 Background: A polygenic risk score (PRS) consisting of 313 single nucleotide polymorphisms (PRS313) is associated with risk of breast cancer and contralateral breast cancer. One of the most promising clinical applications for the use of PRS is to provide a personalized risk assessment to individualize breast cancer screening programs. This study aimed to evaluate the association of the PRS313 with clinical-pathological characteristics and survival of breast cancer. Methods: Women of European ancestry with invasive breast cancer were included, 98,397 women from the Breast Cancer Association Consortium (BCAC) and 683 women from the MINDACT trial. Associations between PRS313 (continuous, per SD) and clinical-pathological characteristics, including the 70-gene signature for patients included in MINDACT, were evaluated with logistic regression analyses. Associations of PRS313 with overall survival (OS), breast cancer-specific survival (BCSS) and distant metastasis-free interval (DMFI) were evaluated with Cox regression analyses, adjusted for clinical-pathological characteristics and treatment. Results: The PRS313 was associated with favorable tumor characteristics. In BCAC, increasing PRS313 was mostly associated with lower grade, hormone receptor-positive tumors, and with smaller tumor size. In MINDACT, PRS313 was associated with a low risk 70-gene signature, but the association was attenuated after adjustment for clinical-pathological characteristics. In BCAC, univariable analyses showed an association of PRS313 with better survival, hazard ratio (HR) per unit SD increase of PRS313 for OS: 0.96 (95% confidence interval (CI): 0.94-0.97), for BCSS HR: 0.96 (95% CI: 0.94-0.98) and for DMFI HR: 0.98 (95% CI: 0.96-1.00). The association in the unadjusted analysis was explained by differences in clinical-pathological characteristics (and treatment) and disappeared after adjustment: OS HR: 1.01 (95% CI: 0.98-1.05), BCSS HR: 1.02 (95% CI: 0.98-1.07) and DMFI HR: 1.03 (95% CI: 0.99-1.07). Conclusions: An increased PRS313 is associated with favorable tumor characteristics but was not independently associated with prognosis. This information is crucial input for modelling effective stratified screening programs, especially in the current era of optimized (systemic) treatments. Given the significant increase in breast cancer risk associated with increasing PRS313, absolute breast cancer mortality will still be higher for women with higher PRS313.

Purpose Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC. Patients and Methods Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations. Results Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P < .001) and had higher-grade tumors (P = .01) than those without mutations. Conclusion Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives.

for this article http://dx.doi.org/10.1016/j.juro.2013.08.101 available at http://jurology.com/ Editorial Comment: As we begin to better understand the influence of specific genetic mutations on prostate carcinogenesis, it is critically important to define the relationship of such mutations with disease outcome. To date, reports on the relationship between BRCA mutations and prostate cancer risk and outcome have been inconsistent, and at times contradictory. In this study the authors report a substantially worsened outcome for men with vs without germline BRCA1/2 mutations. Importantly these men presented with not only more advanced stage, but also higher Gleason score, suggesting phenotype rather than delay in diagnosis. In the setting of a recent report of a man undergoing prophylactic prostatectomy due to BRCA mutation this article offers guidance to the many men with known BRCA mutations who are unclear about the role of early intervention. Samir S. Taneja, M.D. Re: Intermittent versus Continuous Androgen Deprivation in Prostate Cancer M. Hussain, C. M. Tangen, D. L. Berry, C. S. Higano, E. D. Crawford, G. Liu, G. Wilding, S. Prescott, S. Kanaga Sundaram, E. J. Small, N. A. Dawson, B. J. Donnelly, P. M. Venner, U. N. Vaishampayan, P. F. Schellhammer, D. I. Quinn, D. Raghavan, B. Ely, C. M. Moinpour, N. J. Vogelzang and I. M. Thompson, Jr. Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan N Engl J Med 2013; 368: 1314e1325. Abstract for this article http://dx.doi.org/10.1016/j.juro.2013.08.102 available at http://jurology.com/ Editorial Comment: This study compared intermittent and continuous androgen deprivation therapy in men with demonstrated metastatic disease using a noninferiority trial design. The findings do not confirm noninferiority, unlike the recently published study in which men with increasing prostate specific antigen after primary therapy were compared using a similar trial design. It is noteworthy that failure to show noninferiority does not imply superiority of continuous androgen deprivation, as the trial is not powered or designed to demonstrate this finding. Differences in trial 0022-5347/13/1906-2093/0 THE JOURNAL OF UROLOGY © 2013 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. http://dx.doi.org/10.1016/j.juro.2013.08.101 Vol. 190, 2093-2096, December 2013 Printed in U.S.A. www.jurology.com j 2093 2094 PROSTATE CANCER outcomes are not easily explained, but may simply be a function of the differences in disease stage at treatment. Similar to the previous study, improvements in quality of life were noted but were shortlived and limited. This study continues to call into question the true value of intermittent therapy, particularly in men with measurable metastatic disease. Samir S. Taneja, M.D. Re: Impact of Cabazitaxel on 2-Year Survival and Palliation of Tumour-Related Pain in Men with Metastatic Castration-Resistant Prostate Cancer Treated in the TROPIC Trial A. Bahl, S. Oudard, B. Tombal, M. Ozg€ uroglu, S. Hansen, I. Kocak, G. Gravis, J. Devin, L. Shen, J. S. de Bono and A. O. Sartor; TROPIC Investigators Bristol Haematology and Oncology Centre, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom Ann Oncol 2013; 24: 2402e2408. Abstract for this article http://dx.doi.org/10.1016/j.juro.2013.08.103 available at http://jurology.com/for this article http://dx.doi.org/10.1016/j.juro.2013.08.103 available at http://jurology.com/ Editorial Comment: In this updated followup of the TROPIC trial (Cabazitaxel for the Treatment of Metastatic Castration-Resistant Prostate Cancer) cabazitaxel provided a survival advantage over mitoxantrone in men with castration resistant prostate cancer progressing after docetaxel therapy. Many in our field question the relative value of administering chemotherapy to patients with endstage disease for a few months of additional survival. The authors importantly demonstrate prolonged survival in a subset of these men, with cabazitaxel therapy predicting a greater likelihood of survival of 2 years or more, as well as decreased likelihood of pain and reduced analgesic use. Samir S. Taneja, M.D. Re: Androgen-Deprivation Therapy Alone or with Docetaxel in Non-Castrate Metastatic Prostate Cancer (GETUG-AFU 15): A Randomised, Open-Label, Phase 3 Trial G. Gravis, K. Fizazi, F. Joly, S. Oudard, F. Priou, B. Esterni, I. Latorzeff, R. Delva, I. Krakowski, B. Laguerre, F. Rolland, C. Th eodore, G. Deplanque, J. M. Ferrero, D. Pouessel, L. Mourey, P. Beuzeboc, S. Zanetta, M. Habibian, J. F. Berdah, J. Dauba, M. Baciuchka, C. Platini, C. Linassier, J. L. Labourey, J. P. Machiels, C. El Kouri, A. Ravaud, E. Suc, J. C. Eymard, A. Hasbini, G. Bousquet and M. Soulie Medical Oncology and Biostatistics, Institut Paoli-Calmettes, Marseille, France Lancet Oncol 2013; 14: 149e158. Abstract for this article http://dx.doi.org/10.1016/j.juro.2013.08.104 available at http://jurology.com/ Editorial Comment: Since improved survival has been observed in men with castration resistant prostate cancer treated with docetaxel, there has been a desire to consider the use of chemotherapy at earlier stages of the disease. While perhaps desirable to prolong therapeutic response and survival in men with metastatic disease before chemotherapy or hormone therapy, it is unclear if these men would respond given the differences in disease biology. This study shows no improvement in survival among men treated with up to 9 cycles of docetaxel at the initiation of androgen deprivation therapy, with a substantial cost in terms of toxicity. It is unclear whether modifications in administration scheme or dosing, or the addition of prednisone might impact outcome. Samir S. Taneja, M.D.

1539Background: Advances in massively parallel sequencing technologies have made multigene panels affordable and have revolutionized genetic testing for hereditary breast and ovarian cancer. Throug...

Purpose To determine the prevalence of adenomatous and hyperplastic polyps in a large cohort of individuals with a germline mutation in a mismatch repair (MMR) gene, the major genetic determinant of hereditary nonpolyposis colorectal cancer (HNPCC). These prevalences have been estimated previously in smaller studies, and the results have been found to be variable. Patients and Methods Colorectal Adenoma/Carcinoma Prevention Programme 2 trial is a chemoprevention trial in people classified as having HNPCC. The 695 patients with a proven germline MMR mutation and documented screening history before the chemoprevention study were the focus of this study. The number, histology, size, and location of polyps found at the participants' first ever colonoscopy were analyzed in a cross-sectional study. Results Seventy-four patients (10.6%) were found to have at least one adenoma at first colonoscopy, whereas 37 (5.3%) had at least one hyperplastic polyp. The frequency of an adenoma at first colonoscopy increased from 5.0% (95% CI, 2.8% to 8.3%) in patients younger than 35 years old to 18.9% (95% CI, 9.4% to 32.0%) in patients age at least 55 years (P = .0001 for trend). No such trend was observed for hyperplastic polyps. No sex differences were found for either type of polyp. A marginal association was found between the co-occurrence of adenomas and hyperplastic polyps. Adenomas tended to be more proximally distributed through the colon, whereas hyperplastic polyps tended to be located in the distal colon. Conclusion Adenoma prevalence increases with age among MMR mutation carriers, whereas hyperplastic polyp prevalence is consistent. No sex differences were observed for either type of lesion.

5507^ Background: Annual transvaginal ultrasound (TVS) and serum CA125 screening for women at high-risk of Ovarian/Fallopian tube cancer (OC/FTC) in Phase 1 of UKFOCSS lacked sensitivity for early stage disease but downstaged disease volume and may have improved optimal debulking rates. More frequent screening might provide greater benefits. Here we report the final results of 4-monthly screening in one of the largest such trials worldwide. Methods: Between 14/06/2007 and 29/03/2012, 4,531 women at an estimated ≥10% lifetime risk of OC/FTC were recruited and screened by 42 UK centres for 14,263 women screen years. Screening comprised 4-monthly CA125 tests analysed by a risk of ovarian cancer algorithm, adjusted for menopausal status. TVS was annual in those with normal algorithm results, but was triggered sooner if results were non-normal. Women with suspicious scan and/or algorithm results were referred for consideration of surgical intervention. Participants were followed prospectively by centres, questionnaire and national cancer registries. Data was censored 365 days after final screen, withdrawal or death. Clinical trial information: 32794457.