Danny Vesprini

Long-Term Follow-Up of a Large Active Surveillance Cohort of Patients With Prostate Cancer

PURPOSE Active surveillance is increasingly accepted as a treatment option for favorable-risk prostate cancer. Long-term follow-up has been lacking. In this study, we report the long-term outcome of a large active surveillance protocol in men with favorable-risk prostate cancer. PATIENTS AND METHODS In a prospective single-arm cohort study carried out at a single academic health sciences center, 993 men with favorable- or intermediate-risk prostate cancer were managed with an initial expectant approach. Intervention was offered for a prostate-specific antigen (PSA) doubling time of less than 3 years, Gleason score progression, or unequivocal clinical progression. Main outcome measures were overall and disease-specific survival, rate of treatment, and PSA failure rate in the treated patients. RESULTS Among the 819 survivors, the median follow-up time from the first biopsy is 6.4 years (range, 0.2 to 19.8 years). One hundred forty-nine (15%) of 993 patients died, and 844 patients are alive (censored rate, 85.0%). There were 15 deaths (1.5%) from prostate cancer. The 10- and 15-year actuarial cause-specific survival rates were 98.1% and 94.3%, respectively. An additional 13 patients (1.3%) developed metastatic disease and are alive with confirmed metastases (n = 9) or have died of other causes (n = 4). At 5, 10, and 15 years, 75.7%, 63.5%, and 55.0% of patients remained untreated and on surveillance. The cumulative hazard ratio for nonprostate-to-prostate cancer mortality was 9.2:1. CONCLUSION Active surveillance for favorable-risk prostate cancer is feasible and seems safe in the 15-year time frame. In our cohort, 2.8% of patients have developed metastatic disease, and 1.5% have died of prostate cancer. This mortality rate is consistent with expected mortality in favorable-risk patients managed with initial definitive intervention.

V89L polymorphism of type-2, 5-alpha reductase enzyme gene predicts prostate cancer presence and progression

OBJECTIVES The valine (V) to leucine (L) polymorphism of the SRD5A2 gene is associated with 5-alpha reductase-2 activity; patients with the V allele have high activity and patients with the L allele have low activity. We examined whether this polymorphism predicts the presence of prostate cancer in 320 men without cancer who underwent biopsy and cancer progression in 318 men who underwent radical prostatectomy. METHODS The effect of the SRD5A2 gene in predicting the presence of prostate cancer was examined using logistic regression analysis, controlling for established risk factors. The effect of the SRD5A2 gene in predicting prostate cancer progression was examined using a nested, matched, case-control design. Most of the participants were white. RESULTS Of the 320 men, 158 (49.4%) were found on biopsy to have prostate cancer. The overall distribution of the V/V, V/L, and L/L genotypes was 47.5%, 42.5%, and 10.0%, respectively. The adjusted odds ratio for having prostate cancer for patients with at least one V allele was 2.53 compared with patients with the L/L genotype (P = 0.03). Of the 318 patients with cancer, 80 had biochemically detected recurrence and 238 had no evidence of recurrence. The odds ratio for progression for patients with at least one V allele was 3.32 (95% confidence interval 1.67 to 6.62, P = 0.0006) compared with patients with the L/L genotype. CONCLUSIONS Men who have the V allele of the SRD5A2 gene have a twofold increase in the risk of prostate cancer development and an additional twofold increase in the risk of progression compared with men with the L/L genotype.

HPC2 Variants and Screen-Detected Prostate Cancer

Two studies have reported significant associations between susceptibility to prostate cancer and two common missense variants of the HPC2/ELAC2 gene, with estimated relative risks in the range of two- to threefold. We investigated whether these polymorphisms could be informative in the prediction of the presence of prostate cancer in men undergoing prostatic biopsy for the evaluation of an elevated serum-PSA level (> or = 4.0 ng/ml). We genotyped 944 men who underwent a prostate biopsy at our institution, as well as a control population of 922 healthy, unselected women from the same population. The prevalence of the HPC2 Ala541Thr allele was similar in men with prostate cancer (6.3%), men with other prostatic conditions (6.8%), and healthy women (6.3%) (P = .83). We conclude that HPC2 genotyping is unlikely to be a useful adjunct to PSA in the prediction of the presence of biopsy-detected prostate cancer in asymptomatic men.

Intron variants of the p53 gene are associated with increased risk for ovarian cancer but not in carriers of BRCA1 or BRCA2 germline mutations

SummaryTwo biallelic polymorphisms in introns 3 and 6 of the p53 gene were analysed for a possible risk-modifying effect for ovarian cancer. Germline DNA was genotyped from 310 German Caucasian ovarian cancer patients and 364 healthy controls. We also typed 124 affected and 276 unaffected female carriers with known deleterious BRCA1 or BRCA2 germline mutation from high-risk breast-ovarian cancer families. Genotyping was based on PCR and high-resolution gel electrophoresis. German ovarian cancer patients who carried the rare allele of the MspI restriction fragment length polymorphism (RELP) in intron 6 were found to have an overall 1.93-fold increased risk (95% confidence internal (CI) 1.27–2.91) which further increased with the age at diagnosis of 41–60 years (odds ratio (OR) 2.71, 95% CI 1.10–6.71 for 41–50 and OR 2.44, 95% CI 1.12–5.28 for 51–60). The 16 bp duplication polymorphism in intron 3 was in a strong linkage to the MspI RFLP. In BRCA1 or BRCA2 mutation carriers, no difference in allele frequency was observed for carriers affected or unaffected with ovarian cancer. Our data suggest that intronic polymorphisms of the p53 gene modify the risk for ovarian cancer patients but not in carriers with BRCA1 or BRCA2 mutations.

A prospective comparison of MRI‐US fused targeted biopsy versus systematic ultrasound‐guided biopsy for detecting clinically significant prostate cancer in patients on active surveillance

In active surveillance (AS) patients: (i) To compare the ability of a multiparametric MRI (mpMRI)‐ultrasound biopsy system to detect clinically significant (CS) prostate cancer with systematic 12‐core biopsy (R‐TRUSBx), and (ii) To assess the predictive value of mpMRI with biopsy as the reference standard.

Active Surveillance for Intermediate Risk Prostate Cancer: Survival Outcomes in the Sunnybrook Experience

PURPOSE To assess the applicability of active surveillance in patients with intermediate risk prostate cancer, we compared the survival outcomes of patients with low risk and intermediate risk disease. MATERIALS AND METHODS Active surveillance was offered to all patients with low risk (cT1-T2b and Gleason score 6 and prostate specific antigen 10 ng/ml or less) and select intermediate risk disease (age greater than 70 years with cT2c or prostate specific antigen 15 ng/ml or less, or Gleason score 3+4 or less). Data from November 1995 to May 2013 were extracted from a prospectively collected database. The primary outcome was metastasis-free survival, and secondary outcomes were overall survival, cause specific survival and treatment-free survival. RESULTS A total of 213 intermediate risk and 732 low risk cases were identified. Median age was 72 years (IQR 67.3, 76.8) in the intermediate risk cohort and 67 years (IQR 60.6, 71.9) in the low risk group. Median followup was comparable (6.7 years for intermediate risk vs 6.5 years for low risk). Gleason 7 disease comprised 60% of the intermediate risk cohort. The 15-year metastasis-free, overall, cause specific and treatment-free survival rates were inferior in the intermediate risk group (metastasis-free survival HR 3.14, 95% CI 1.51-6.53, p=0.001, 82% for intermediate risk vs 95% for low risk). On further evaluation the estimated 15-year metastasis-free survival for cases of Gleason 6 or less with prostate specific antigen less than 10 ng/ml was 94%, Gleason 6 or less with prostate specific antigen 10 to 20 ng/ml was 94%, Gleason 3+4 with prostate specific antigen 20 ng/ml or less was 84% and Gleason 4+3 with prostate specific antigen 20 ng/ml or less was 63%. CONCLUSIONS These data support the use of active surveillance in low risk and intermediate risk cases of Gleason 6 but not Gleason 7 prostate cancer. Multiparametric magnetic resonance imaging and novel biomarkers might be vital in detecting favorable Gleason 7 disease.

Comparing Prostate Specific Antigen Triggers for Intervention in Men With Stable Prostate Cancer on Active Surveillance

PURPOSE We determined the proportion of men with nonprogressive prostate cancer on active surveillance who had a trigger for treatment using various measures of prostate specific antigen kinetics. MATERIALS AND METHODS A prospective phase II study of patients with favorable clinical parameters (stage T1b-T2b N0M0, Gleason sum 7 or less, prostate specific antigen 15 ng/ml or less) on active surveillance was initiated in 1995. Those patients considered at high risk for progression were offered radical intervention. The remaining patients were closely monitored and formed the cohort for this study. We calculated the proportion and frequency of patients who had a trigger for treatment based on the various prostate specific antigen triggers (prostate specific antigen doubling time, prostate specific antigen velocity, prostate specific antigen threshold). RESULTS Of 450 patients followed on surveillance 305 remained on active surveillance without definitive intervention. None of these 305 patients have died of prostate cancer or have had symptomatic metastatic disease develop. Median followup was 6.8 years. The proportion of patients who would have had a trigger for treatment ranged from 14% to 42% for the threshold triggers, 37% to 50% for the prostate specific antigen doubling time triggers and 42% to 84% for the velocity triggers. CONCLUSIONS Almost all of the prostate specific antigen triggers examined in this study would have led to high rates of trigger for treatment. More work is needed to identify a trigger that better strikes the balance between recommending treatment for patients at high risk for progression and minimizing treatment for those at low risk for progression.

Progesterone receptor variant increases ovarian cancer risk in BRCA1 and BRCA2 mutation carriers who were never exposed to oral contraceptives.

Oral contraceptives have been shown to be protective against hereditary ovarian cancer. The variant progesterone receptor allele named PROGINS is characterized by an Alu insertion into intron G and two additional mutations in exons 4 and 5. The PROGINS allele codes for a progesterone receptor with increased stability and increased hormone-induced transcriptional activity. We studied the role of the PROGINS allele as a modifying gene in hereditary breast and ovarian cancer. The study included 195 BRCA1 and BRCA2 carriers with a prior diagnosis of ovarian cancer, 392 carriers with a diagnosis of breast cancer and 249 carriers with neither cancer. Fifty-eight women had both forms of cancer. Five hundred and ninety-five women had a BRCA1 mutation and 183 women had a BRCA2 mutation. Overall, there was no association between disease status and the presence of the PROGINS allele. Information on oral contraception use was available for 663 of the 778 carriers of BRCA1 or BRCA2 mutations. Among the 449 subjects with a history of oral contraceptive use (74 cases and 365 controls), no modifying effect of PROGINS was observed [odds ratio (OR) 0.8; 95% confidence interval (CI) 0.5-1.3]. Among the 214 carriers with no past exposure to oral contraceptives, the presence of one or more PROGINS alleles was associated with an OR of 2.4 for ovarian cancer, compared to women without ovarian cancer and with no PROGINS allele (P = 0.004; 95% CI 1.4-4.3). The association was present after adjustment for ethnic group and for year of birth.

Gleason Upgrading with Time in a Large Prostate Cancer Active Surveillance Cohort

PURPOSE We report the percentage of patients on active surveillance who had disease pathologically upgraded and factors that predict for upgrading on surveillance biopsies. MATERIALS AND METHODS Patients in our active surveillance database with at least 1 repeat prostate biopsy were included. Histological upgrading was defined as any increase in primary or secondary Gleason grade on repeat biopsy. Multivariate analysis was used to determine baseline and dynamic factors associated with Gleason upgrading. This information was used to develop a nomogram to predict for upgrading or treatment in patients electing for active surveillance. RESULTS Of 862 patients in our cohort 592 had 2 or more biopsies. Median followup was 6.4 years. Of the patients 20% were intermediate risk, 0.3% were high risk and all others were low risk. During active surveillance 31.3% of cases were upgraded. On multivariate analysis clinical stage T2, higher prostate specific antigen and higher percentage of cores involved with disease at the time of diagnosis predicted for upgrading. A total of 27 cases (15% of those upgraded) were Gleason 8 or higher at upgrading, and 62% of all 114 upgraded cases went on to have active treatment. The nomogram incorporated clinical stage, age, prostate specific antigen, core positivity and Gleason score. The concordance index was 0.61. CONCLUSIONS In this large re-biopsy cohort with medium-term followup, most cases have not been pathologically upgraded to date. A model predicting for upgrading or radical treatment was developed which could be useful in counseling patients considering active surveillance for prostate cancer.

Polymorphisms in GSTM1, GSTT1 and CYP1A1 and risk of pancreatic adenocarcinoma

A prospective study of 149 unselected incident cases of pancreatic adenocarcinoma and 146 ethnically-matched controls found no associations between GSTM1 (adjusted odds ratio (AOR) 1.14), GSTT1 (AOR: 1.19) and CYP1A1 (AOR: 1.08) polymorphisms and pancreatic cancer susceptibility. Smoking and drinking status did not affect results. These polymorphisms do not appear to be important gene modifiers in pancreatic cancer.