Karen Chadwick

Comparison of risk calculators from the Prostate Cancer Prevention Trial and the European Randomized Study of Screening for Prostate Cancer in a contemporary Canadian cohort

Study Type – Prognosis (inception cohort)

Plasma osteopontin as a biomarker of prostate cancer aggression: relationship to risk category and treatment response

Background:High plasma osteopontin (OPN) has been linked to tumour hypoxia, metastasis, and poor prognosis. This study aims to assess whether plasma osteopontin was a biomarker of increasing progression within prostate cancer (PCa) prognostic groups and whether it reflected treatment response to local and systemic therapies.Methods:Baseline OPN was determined in men with localised (n=199), locally recurrent (n=9) and castrate-resistant, metastatic PCa (CRPC-MET; n=37). Receiver-operating curves (ROC) were generated to describe the accuracy of OPN for distinguishing between localised risk groups or localised vs metastatic disease. We also measured OPN pre- and posttreatment, following radical prostatectomy, external beam radiotherapy (EBRT), androgen deprivation (AD) or taxane-based chemotherapy.Results:The CRPC-MET patients had increased baseline values (mean 219; 56–513 ng ml−1; P<0.0001) compared with the localised, non-metastatic group (mean 72; 12–438 ng ml−1). The area under the ROC to differentiate localised vs metastatic disease was improved when OPN was added to prostate-specific antigen (PSA) (0.943–0.969). Osteopontin neither distinguished high-risk PCa from other localised PCa nor correlated with serum PSA at baseline. Osteopontin levels reduced in low-risk patients after radical prostatectomy (P=0.005) and in CRPC-MET patients after chemotherapy (P=0.027), but not after EBRT or AD.Conclusion:Plasma OPN is as good as PSA at predicting treatment response in CRPC-MET patients after chemotherapy. Our data do not support the use of plasma OPN as a biomarker of increasing tumour burden within localised PCa.

Clinical significance of the positive surgical margin based upon location, grade, and stage

Prostate cancer remains a challenge due to its incidence and radical prostatectomy continues to be a major treatment option for men with potentially curable disease who have a life expectancy over a decade. This article will address the common problem of positive surgical margins and the impact of them on patient outcome. Through these we can examine relevant clinical trials that have attempted to address this issue and offer some guided to therapy among men with this clinical problem. Close margins are probably of no significance and will not be addressed. Our recommendations take into account the current level of medical evidence, and are balanced with anticipated adverse effects of treatment. They may change over time once definitive clinical trials are completed. In brief we believe those with positive margins and PT2 we advocate close observation with the aim of early salvage radiotherapy if necessary. Those with PT3a and focally positive margins with low/intermediate grade tumors are at moderate risk of biochemical failure so should be managed like PT2 patients. However those with high-grade disease should be offered adjuvant radiotherapy. Similarly those with PT3a margin positive extensive or multiple site disease should have adjuvant radiotherapy. PT3B margin positive patients should be offered radiotherapy. PT4 with bladder neck only margin positive can probably be observed.

Germline mutations in the kallikrein 6 region and predisposition for aggressive prostate cancer

Background There is a need for markers that can specifically identify individuals at increased risk of harboring aggressive forms of prostate cancer (PCa). Methods We surveyed the Kallikrein ( KLK ) region ( KLK 1-15) for single-nucleotide polymorphisms (SNPs) associated with aggressive PCa (Gleason Score ≥ 8) in 1858 PCa patients. Discovery cohorts (Swiss arm of the European Randomized Study of Screening for PCa, n = 379; Toronto, Canada, n = 540) and a validation cohort (Prostate, Lung, Colorectal and Ovarian [PLCO] screening trial, n = 939) were analyzed. Fine-mapping within the KLK region was carried out by genotyping and imputation in the discovery cohort, whereas PLCO data were provided through database of Genotypes and Phenotypes ( dbGaP ). The influence of SNPs of interest on biochemical-free survival was evaluated in a cohort of localized PCa from the International Cancer Genome Consortium (ICGC; n = 130) analyzed with next-generation sequencing. Single- and multi-SNP association studies, as well as haplotype analyses, were performed. All statistical tests were two-sided. Results Several SNPs in very strong linkage disequilibrium in the KLK 6 region and located within the same haplotype (rs113640578, rs79324425, rs11666929, rs28384475, rs3810287), identified individuals at increased risk of aggressive PCa in both discovery (odds ratio [OR] = 3.51-3.64, 95% confidence interval [CI] = 2.01 to 6.36, P = 1.0x10 -5 -8.4x10 -6 ) and validation (OR = 1.89-1.96, 95% CI = 0.99 to 3.71, P = .04-.05) cohorts. The overall test of haplotype association was highly statistically significant in each cohort ( P = 3.5x10 -4 and .006, respectively) and in the three data sets combined ( P = 2.3x10 -5 ). These germline SNPs independently predicted relapse in the ICGC cohort (hazard ratio = 3.15, 95% CI = 1.57 to 6.34, P = .001). Conclusions Our fine-mapping study has identified novel loci in the KLK 6 region strongly associated with aggressive PCa.

Testosterone Responders to Continuous Androgen Deprivation Therapy Show Considerable Variations in Testosterone Levels on Followup: Implications for Clinical Practice

Purpose We determined whether men on continuous androgen deprivation therapy who achieve testosterone less than 0.7 nmol/l demonstrate subsequent testosterone elevations during followup and whether such events predict worse oncologic outcomes. Materials and Methods We evaluated a random, retrospective sample of 514 patients with prostate cancer treated with continuous androgen deprivation therapy in whom serum testosterone was less than 0.7 nmol/l at University Health Network between 2007 and 2016. Patients were followed from the date of the first testosterone measurement of less than 0.7 nmol/l to progression to castrate resistance, death or study period end. Study outcomes were the development of testosterone elevations greater than 0.7, greater than 1.1 and greater than 1.7 nmol/l, and progression to a castrate resistant state. Survival curves were constructed to determine the rate of testosterone elevations. Multivariate Cox regression analysis was done to assess whether elevations predicted progression to castrate resistance. Results Median patient age was 74 years and median followup was 20.3 months. Within 5 years of followup 82%, 45% and 18% of patients had subsequent testosterone levels greater than 0.7, greater than 1.1 and greater than 1.7 nmol/l, respectively. In 96% to 100% of these patients levels less than 0.7 nmol/l were subsequently reestablished within 5 years. No patient baseline characteristic was associated with elevations and elevations were not a significant predictor of progression to a castrate resistant state. Conclusions Men on continuous androgen deprivation therapy in whom initial testosterone is less than 0.7 nmol/l frequently show subsequent elevations in serum testosterone. Such a development should not trigger an immediate response from physicians as these events are prognostically insignificant with regard to oncologic outcomes. Levels are eventually reestablished at less than 0.7 nmol/l.

PD24-08 TESTOSTERONE RESPONDERS TO CONTINUOUS ANDROGEN DEPRIVATION THERAPY EXHIBIT CONSIDERABLE VARIATION IN TESTOSTERONE LEVELS ON FOLLOW UP

receiving ADT. We collected their clinical and demographic data, and whether BT was administered. Because our study period preceded the approval of novel agents for mCP and the shift to upfront chemotherapy, we defined castrate resistance as the initiation of chemotherapy. Statistical analysis was performed using SAS v9.3 (Cary, NC). RESULTS: A total of 2563 men were treated with ADT for mCP, and BT was administered to 431 (16.8%). Utilization of BT increased significantly during the study period, from 5.9% in 2004 to 35.2% in 2011 (p<0.01). On multivariate analysis, men had increased odds of receiving BT if year of diagnosis was later than 2008 or an oncologist was involved in their care, and decreased odds of BT if receiving care in a less urban area (p<0.05, Table 1). Among the subset of men with mCRCP (433, 16.9%), BT was administered to 136 (31.4%). On multivariate analysis, age 80-85 and diagnosis year later than 2010 were associated with increased odds of BT (OR 2.57 and 1.57, respectively; p1⁄40.01). Adverse events related to BT were rare, with osteonecrosis of the jaw occurring in 7 (1.6%) and hypocalcemia in 34 (8.0%). CONCLUSIONS: Utilization of BT among men with mCP is increasing, though the overall usage of these medications remains low. Among men with mCRCP, only 31.4% received bone health treatments in accordance with NCCN guidelines. As novel anti-androgens expand the role of urologists in management of mCRCP, careful consideration of appropriate management of bone health must not be overlooked.

MP77-18 WHAT FALSE NEGATIVE RATE OF NON-INVASIVE TESTING ARE ACTIVE SURVEILLANCE PATIENTS AND URO-ONCOLOGISTS WILLING TO ACCEPT IN ORDER TO AVOID PROSTATE BIOPSY?

on AS must undergo PSA testing and repeated biopsies over time in all proposed protocols and patients are subjected to discomfort and anxiety as well as to the complications of repeated biopsies. We tried to identify the predictors of progression-free survival (PFS) at a single institution AS program in order to identify patients in whom repeated biopsies could be avoided or reduced in frequency. METHODS: Between 2009 and 2016, 235 consecutive patients affected by low-risk PCa according to PRIAS criteria (cT1/T2a; PSA<10 ng/ml; PSA density <0.2; Gleason score <7; <3 positive cores) were enrolled in our AS program. Tumor progression was defined as pathological upgrading (Gleason >6 or >2 positive cores) at repeated yearly biopsies. First, Kaplan-Meier analyses were used to quantify progression-free survival at 1, 3 and 5 years, respectively. Second, we identified patients who were progression-free at 3 years of follow-up. Finally, univariable and multivariable logistic regression analyses were used to predict 3-year PFS. Covariates consisted of age, total PSA, clinical stage (cT) and number of positive cores at the time of enrolment as well as negative (no cancer) 1-year biopsy. RESULTS: Progression-free survival rate was 85%, 55%, and 40% at 1, 3 and 5 years, respectively. Median follow-up was 19 months. Overall, 56 (23.8%) patients were progression-free at 3 years of followup. Median number of cores at enrolment in AS program was 16 (IQR: 14-20), while median number of cores at first-year biopsy was 18 (IQR: 14-20). At univariable analyses, total PSA and negative 1-year biopsy were significant predictors of 3-year PFS (all p<0.05). Patients with negative biopsy at 1 year had a 3-year PFS of 75.8 vs. 29.0% in those with positive biopsy at 1-year. These results were confirmed at multivariable analyses, where a negative 1-year biopsy represented the only independent predictor of 3-year PFS (OR: 2.47; p1⁄40.04). CONCLUSIONS: The first biopsy after enrolment in AS program is an important predictor of PCa progression in the first 3 years in men on AS. Negative findings at 1-year biopsy suggest a high chance of 3-year PFS. Patients with negative 1-year biopsy could be followedup with less stringent biopsy protocol, in order to reduce possible biopsy-related side effects and discomfort.

PD65-01 GERMLINE MUTATIONS IN THE KALLIKREIN 6 REGION AND PREDISPOSITION FOR AGGRESSIVE PROSTATE CANCER

Laurent Briollais, Hilmi Ozcelik, Jingxiong Xu, Toronto, Canada; Maciej Kwiatkowski, Aarau, Switzerland; Emilie Lalonde, Dorota H Sendorek, Neil E Fleshner, Toronto, Canada; Franz Recker, Aarau, Switzerland; Cynthia Kuk, Ekaterina Olkhov-Mitsel, Toronto, Canada; Sevtap Savas, St. John’s, Canada; Sally Hanna, Tristan Juvet, Geoffrey A Hunter, Matt Friedlander, Hong Li, Karen Chadwick, Ioannis Prassas, Antoninus Soosaipillai, Toronto, Canada; Marco Randazzo, Aarau, Switzerland; John Trachtenberg, Ants Toi, Yu-Jia Shiah, Michael Fraser, Theodorus van der Kwast, Robert G Bristow, Bharati Bapat, Eleftherios P. Diamandis, Paul C Boutros, Alexandre R Zlotta*, Toronto, Canada

What false-negative rates of non-invasive testing are active surveillance patients and uro-oncologists willing to accept in order to avoid prostate biopsy?

INTRODUCTION Repeat prostate biopsies in active surveillance patients are associated with significant complications. Novel imaging and blood/urine-based non-invasive tests are being developed to better predict disease grade and volume progression. We conducted a theoretical study to determine what test performance characteristics and costs would a non-invasive test(s) require in order for patients and their physicians to comfortably avoid biopsy. METHODS Surveys were administered to two populations to determine an acceptable false-negative rate and cost for such test(s). Active surveillance patients were recruited at time of followup in clinic at Princess Margaret Cancer Centre. Physician members of the Society of Urological Oncology were targeted via an online survey. Participants were questioned about their demographics and other characteristics that might influence chosen error rates and cost. RESULTS 136 patients and 670 physicians were surveyed, with 130 (95.6%) and 104 (15.5%) responses obtained, respectively. A vast majority of patients (90.6%) were comfortable with a non-invasive test(s) in place of biopsy, with 64.8% accepting a false-negative rate of 5-20%. Most physicians (93.3%) were comfortable with a non-invasive test, with 77.9% accepting a rate of 5-20%. Most patients and physicians felt that a cost of less than

The association of male pattern baldness and risk of cancer and high-grade disease among men presenting for prostate biopsy

1000 per administration would be reasonable. CONCLUSIONS Most patients/physicians are comfortable with a non-invasive test(s). Although a 5% error rate seems acceptable to many, a substantial subset feels that 99% or higher negative predictive value is required. Thus, a personalized approach with shared decision-making between patients and physicians is essential to optimize patient care in such situations.