The Heritability of Prostate Cancer in the Nordic Twin Study of Cancer

BACKGROUND: Prostate cancer is thought to be the most heritable cancer, although little is known about how this genetic contribution varies across age. METHODS: To address this question, we undertook the world's largest prospective study in the Nordic Twin Study of Cancer cohort, including 18,680 monozygotic and 30,054 dizygotic same sex male twin pairs. We incorporated time-to-event analyses to estimate the risk concordance and heritability while accounting for censoring and competing risks of death, essential sources of biases that have not been accounted for in previous twin studies modeling cancer risk and liability. RESULTS: The cumulative risk of prostate cancer was similar to that of the background population. The cumulative risk for twins whose co-twin was diagnosed with prostate cancer was greater for MZ than for DZ twins across all ages. Among concordantly affected pairs, the time between diagnoses was significantly shorter for MZ than DZ pairs (median 3.8 versus 6.5 years, respectively). Genetic differences contributed substantially to variation in both the risk and the liability (heritability=58% (95% CI 52%–63%) of developing prostate cancer. The relative contribution of genetic factors was constant across age through late life with substantial genetic heterogeneity even when diagnosis and screening procedures vary. CONCLUSIONS: Results from the population based twin cohort, indicate a greater genetic contribution to the risk of developing prostate cancer when addressing sources of bias. The role of genetic factors is consistently high across age IMPACT: Findings impact the search for genetic and epigenetic markers and frame prevention efforts

Characteristics of Patients in SPCG-15-A Randomized Trial Comparing Radical Prostatectomy with Primary Radiotherapy plus Androgen Deprivation Therapy in Men with Locally Advanced Prostate Cancer

Background: There is no high-grade evidence for surgery as primary treatment for locally advanced prostate cancer. The SPCG-15 study is the first randomized trial comparing surgical treatment with radiotherapy. Objective: To describe the baseline characteristics of the first 600 randomized men in the SPCG-15 study. The study will compare mortality and functional outcomes. Design, setting, and participants: This study is a Scandinavian prospective, open, multicenter phase III randomized clinical trial aiming to randomize 1200 men. Intervention: Radical prostatectomy with or without consecutive radiotherapy (experimental) and radiotherapy with neoadjuvant androgen deprivation therapy (standard of care). Outcome measurements and statistical analysis: Cause-specific survival, metastasis-free survival, overall survival, and patient-reported bowel function, sexual health, and lower urinary tract symptoms were measured. Results and limitations: The distribution of characteristics was similar in the two study arms. The median age was 67 yr (range 45-75 yr). Among the operated men, 36% had pT3a stage of disease and 39% had pT3b stage. International Society of Urological Pathology grades 2, 3, 4, and 5 were prevalent in 21%, 35%, 7%, and 27%, respectively. Half of the men (51%) in the surgery arm had no positive lymph nodes. The main limitation is the pragmatic design comparing the best available practice at each study site leading to heterogeneity of treatment regimens within the study arms. Conclusions: We have proved that randomization between surgery and radiotherapy for locally advanced prostate cancer is feasible. The characteristics of the study population demonstrate a high prevalence of advanced disease, well-balanced comparison groups, and a demography mirroring the Scandinavian population of men with prostate cancer at large. Patient summary: This study, which has recruited >600 men, compares radiotherapy with surgery for prostate cancer, and an analysis at the time of randomization indicates that the study will be informative and generalizable to most men with locally advanced but not metastasized prostate cancer. (C) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology.Peer reviewe

Prognostic factors for survival in the phase III TROPIC trial.

102 Background: In TROPIC ( NCT00417079 ) 755 men were randomized (378 cabazitaxel/prednisone [CbzP]; 377 mitoxantrone/prednisone [MP]). Treatment arms were well balanced; ECOG PS 0–1 (93% CbzP vs 91% MP), measurable disease (53% vs 54%), baseline pain (46% vs 45%) and ≤ 6 months from last dose of docetaxel (D) to randomization (62% vs 72%). CbzP significantly improved overall survival (OS) in mCRPC pts who progressed on or after D treatment compared with MP (HR 0.70; CI 0.59–0.83; P &lt; 0.0001). We investigated overall prognosis and performed a multivariate analysis of factors implicated in OS from this robust dataset. Methods: A univariate analysis of a variety of factors followed by a multivariate analysis of all factors was conducted. Interactions with treatment arms were explored. Cox proportional hazard models were used to examine the effect of treatment and prognostic factors on OS. Results: In addition to the significant effect of treatment received, the univariate analysis identified ECOG PS and measurable disease at baseline, time from last dose of D to randomization, time of progression after last D treatment and pain scores at baseline as significant prognostic factors for OS. Interactions of each of these factors with the treatment were not statistically distinct, suggesting that CbzP survival benefit was consistent among the subgroups defined by these factors. After adjustments for all prognostic factors, multivariate analysis identified ECOG PS 2, measurable disease, time of last dose of D to randomization (≤ 6 months vs &gt; 6 months) and presence of baseline pain as statistically significant prognostic factors. Following adjustments, the treatment effect on survival (CbzP vs MP) remained statistically significant (Table). Conclusions: ECOG PS, measurable disease at baseline, time from last D dose to randomization, baseline pain and CbzP treatment predicted OS in patients in the TROPIC study in a multivariate analysis. [Table: see text] </jats:p

Final Analysis of the Ipilimumab Versus Placebo Following Radiotherapy Phase III Trial in Postdocetaxel Metastatic Castration-resistant Prostate Cancer Identifies an Excess of Long-term Survivors

Background: The phase 3 trial CA184-043 evaluated radiotherapy to bone metastases followed by Ipilimumab or placebo in men with metastatic castrate-resistant prostate cancer (mCRPC) who had received docetaxel previously. In a prior analysis, the trial's primary endpoint (overall survival [OS]) was not improved significantly. Objective: To report the final analysis of OS. Design, setting, and participants: A total of 799 patients were randomized to receive a single dose of radiotherapy to one or more bone metastases followed by either Ipilimumab (n = 399) or placebo (n = 400). Outcome measurements and statistical analysis: OS was analyzed in the intention-to-treat population. Prespecified and exploratory subset analyses based on Kaplan-Meier/Cox methodology were performed. Results and limitations: During an additional follow-up of approximately 2.4 yr since the primary analysis, 721/799 patients have died. Survival analysis showed crossing of the curves at 7–8 mo, followed by persistent separation of the curves beyond that point, favoring the ipilimumab arm. Given the lack of proportional hazards, a piecewise hazard model showed that the hazard ratio (HR) changed over time: the HR was 1.49 (95% confidence interval 1.12, 1.99) for 0–5 mo, 0.66 (0.51, 0.86) for 5–12 mo, and 0.66 (0.52, 0.84) beyond 12 mo. OS rates were higher in the ipilimumab versus placebo arms at 2 yr (25.2% vs 16.6%), 3 yr (15.3% vs 7.9%), 4 yr (10.1% vs 3.3%), and 5 yr (7.9% vs. 2.7%). Disease progression was the most frequent cause of death in both arms. In seven patients (1.8%) in the ipilimumab arm and one (0.3%) in the placebo arm, the primary cause of death was reported as study drug toxicity. No long-term safety signals were identified. Conclusions: In this preplanned long-term analysis, OS favored ipilimumab plus radiotherapy versus placebo plus radiotherapy for patients with postdocetaxel mCRPC. OS rates at 3, 4, and 5 yr were approximately two to three times higher in the ipilimumab arm. Patient summary: After longer follow-up, survival favored the group of men who received ipilimumab, with overall survival rates being two to three times higher at 3 yr and beyond