Prostate Testing For Cancer Research Articles

Prevalence of theHOXB13 G84E germline mutation in British men and correlation with prostate cancer risk, tumour characteristics and clinical outcomes

A rare recurrent missense variant in HOXB13 (rs138213197/G84E) was recently reported to be associated with hereditary prostate cancer. Population-based studies have established that, since the frequency of this single-nucleotide polymorphism (SNP) varies between geographic regions, the associated proportion of prostate cancer (PrCa) risk contribution is also highly variable by country. This is the largest comprehensive case-control study assessing the prevalence of the HOXB13 G84E variant to date and is the first in the UK population. We genotyped 8652 men diagnosed with PrCa within the UK Genetic Prostate Cancer Study (UKGPCS) and 5252 healthy men from the UK ProtecT study. HOXB13 G84E was identified in 0.5% of the healthy controls and 1.5% of the PrCa cases, and it was associated with a 2.93-fold increased risk of PrCa [95% confidence interval (CI) 1.94-4.59; P = 6.27 × 10(-8)]. The risk was even higher among men with family history of PrCa [odds ratio (OR) = 4.53, 95% CI 2.86-7.34; P = 3.1 × 10(-8)] and in young-onset PrCa (diagnosed up to the age of 55 years; OR = 3.11, 95% CI 1.98-5.00; P = 6.1 × 10(-7)). There was no significant association between Gleason Score, presenting prostate specific antigen, tumour-node-metastasis (TNM) stage or NCCN risk group and carrier status. HOXB13 G84E was not associated with overall or cancer-specific survival. We found that the polygenic PrCa risk score (PR score), calculated using the 71 known single-nucleotide polymorphisms (SNPs) associated with PrCa and the HOXB13 G84E variant act multiplicatively on PrCa risk. Based on the estimated prevalence and risk, this rare variant explains ∼1% of the familial risk of PrCa in the UK population. The clinical importance of HOXB13 G84E in PrCa management has not been established. This variant was found to have no effect on prognostic implications but could be used for stratifying screening, by identifying men at high risk. Prostate Testing for Cancer and Treatment (ProtecT): NCT02044172. Epidemiology and Molecular Genetics Studies (UKGPCS): NCT01737242.

Physical activity, alcohol consumption, BMI and smoking status before and after prostate cancer diagnosis in the ProtecT trial: opportunities for lifestyle modification.

Associations between certain lifestyle characteristics and prostate cancer risk have been reported, and continuation post-diagnosis can adversely affect prognosis. We explored whether men make spontaneous changes to their physical activity and alcohol intake, body mass index (BMI) and smoking status, following a diagnosis of localised prostate cancer. A detailed diet, health and lifestyle questionnaire was completed by 511 participants within the Prostate Testing for Cancer and Treatment (ProtecT) randomised controlled trial, both before and 9 months after a diagnosis of prostate cancer. Of 177 men who were insufficiently active before their diagnosis (median 0 activity units/week; IQR 0–9), 40.7% had increased their activity by a median of 22 U week−1 (IQR 15–35) 9 months later, and there was weak evidence that men were more active after diagnosis than before (p = 0.07). Men categorised as “working” occupational social class and who were insufficiently active before diagnosis were 2.03 (95%, CI = 1.03–3.99, p = 0.04) times more likely to have increased their physical activity levels compared to men classified as “managerial or professional.” Similarly, men who were insufficiently active pre-diagnosis and with T-stage 2 compared with T-stage 1 prostate cancer were 2.47 (95%, CI = 1.29–4.71, p = 0.006) times more likely to be sufficiently active post-diagnosis. Following diagnosis, there was an overall reduction in alcohol intake (p = 0.03) and the proportion of current smokers (p = 0.09), but no overall change in BMI. We conclude that some men spontaneously change certain lifestyle behaviours on receiving a diagnosis of prostate cancer. For many men, however, additional support through lifestyle interventions is probably required to facilitate and maintain these changes.What’s new?Does cancer diagnosis lead individuals to consider making healthy lifestyle changes? These authors studied men diagnosed with prostate cancer to find out whether they changed their activity level, alcohol consumption, body mass index, or smoking habits after being diagnosed with prostate cancer. They found that some men increased their activity level and/or decreased their alcohol consumption, but not all. As making positive lifestyle changes may improve prognosis, it’s worth looking for ways to encourage newly diagnosed patients to make healthy changes.

Role of information in preparing men for transrectal ultrasound guided prostate biopsy: a qualitative study embedded in the ProtecT trial.

BackgroundThe histological diagnosis of prostate cancer requires a prostate needle biopsy. Little is known about the relationship between information provided to prepare men for transrectal ultrasound guided biopsy (TRUS-Bx) and how men experience biopsy. The objectives were a) to understand men’s experiences of biopsy as compared to their expectations; and b) to propose current evidence-based information for men undergoing TRUS-Bx.MethodsBetween February 2006 and May 2008, 1,147 men undergoing a standardised 10-core transrectal ultrasound guided biopsy protocol under antibiotic cover following a PSA 3.0-19.9 ng/ml in the Prostate Testing for Cancer and Treatment (ProtecT) trial, completed questionnaires about biopsy symptoms. In this embedded qualitative study, in-depth interviews were undertaken with 85 men (mean age 63.6 yrs, mean PSA 4.5 ng/ml) to explore men’s experiences of prostate biopsy and how the experience might be improved. Interview data were analysed thematically using qualitative research methods. Findings from the qualitative study were used to guide selection of key findings from the questionnaire study in developing a patient information leaflet preparing men for biopsy.ResultsAlthough most men tolerated TRUS-Bx, a quarter reported problematic side-effects and anxiety. Side effects were perceived as problematic and anxiety arose most commonly when experiences deviated from information provided. Men who were unprepared for elements of TRUS-Bx procedure or its sequelae responded by contacting health professionals for reassurance and voiced frustration that pre-biopsy information had understated the possible severity or duration of pain/discomfort and bleeding. Findings from questionnaire and interview data were combined to propose a comprehensive, evidence-based patient information leaflet for TRUS-Bx.ConclusionsMen reported anxiety associated with TRUS-Bx or its side-effects most commonly if they felt inadequately prepared for the procedure. Data from this qualitative study and the previous questionnaire study have been used to propose an updated, comprehensive evidence-based set of information for men undergoing TRUS-Bx.Electronic supplementary materialThe online version of this article (doi:10.1186/s12913-015-0729-z) contains supplementary material, which is available to authorized users.

Adherence to dietary and lifestyle recommendations and prostate cancer risk in the prostate testing for cancer and treatment (ProtecT) trial.

The World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) published eight recommendations for cancer prevention, but they are not targeted at prostate cancer prevention. We investigated whether adherence to the WCRF/AICR recommendations and a prostate cancer dietary index is associated with prostate cancer risk. We conducted a nested case-control study of 1,806 prostate-specific antigen (PSA)-detected prostate cancer cases and 12,005 controls in the ProtecT trial. We developed a prostate cancer dietary index by incorporating three dietary factors most strongly associated with prostate cancer. Scores were computed to quantify adherence to the WCRF/AICR recommendations and the prostate cancer dietary index separately. The prostate cancer dietary index score was associated with decreased risk of prostate cancer [OR per 1 score increment: 0.91; 95% confidence interval (CI): 0.84-0.99; Ptrend = 0.04] but the WCRF/AICR index score was not (OR: 0.99; 95% CI: 0.94-1.05; Ptrend = 0.71). There was no heterogeneity in association by prostate cancer stage (P = 0.81) or grade (P = 0.61). Greater adherence to recommendations to increase plant foods (OR per 0.25 index score increment: 0.94; 95% CI: 0.89-0.99; Ptrend = 0.02) and tomato products (OR adherence vs. nonadherence: 0.82; 95% CI: 0.70-0.97; P = 0.02) was inversely associated with overall prostate cancer risk. Adherence to the prostate cancer-specific dietary recommendations was associated with decreased risk of prostate cancer. High intake of plant foods and tomato products in particular may help protect against prostate cancer. Meeting the WCRF/AICR recommendations alone is insufficient for prostate cancer prevention. Additional dietary recommendations should be developed.

Abstract 261: Implications of polygenic risk-stratified screening for prostate cancer on overdiagnosis

Abstract Purpose Personalized screening for prostate cancer with eligibility for screening based on an absolute risk that is dependent on age and polygenic risk-profile would improve the efficiency of the screening program. However, yet there is no evidence from empirical data that such personalized screening strategy would reduce harms of screening, by reducing overdiagnosis and subsequent overtreatment. This study aims at quantifying the probabilities of overdiagnosis by polygenic risk profile. Methods We calculated polygenic risk score based on 66 known prostate cancer susceptibility variants for 17,729 men aged 50-69 years (9,404 men identified with prostate cancer and 8,325 with no cancer) derived from three UK-based ongoing studies: Prostate Testing for Cancer and Treatment (ProtecT), Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH), and UK Genetic Prostate Cancer Study (UKGPCS). We estimated absolute risk of developing prostate cancer dependent on age and polygenic profile for each man. For each quartile of polygenic risk score distribution among the population, we calculated the observed prevalence of screen-detected prostate cancer within ProtecT and the mean absolute risk for clinically detected cancers within SEARCH and UKGPCS. We derived the probabilities of overdiagnosis by quartiles of polygenic risk considering that the observed prevalence is a combination of underlying incidence, the duration of the preclinical detectable period (sojourn time), test sensitivity, and overdiagnosis. Results The polygenic risk score among the population had log-normal distribution with variance of 0.40, with polygenic risk score of -0.63, -0.20, and 0.23 at 25th, 50th and 75th percentile respectively. Quartiles 1 to 4 had 17%, 21%, 25% and 37% of the cases respectively. From the lowest to highest quartile of risk, 42%, 29%, 25% and 19% of the prevalent screen-detected cancers were likely to be overdiagnosed cancers. The proportion of overdiagnosed cases decreased with increasing polygenic risk, with 50% drop in overdiagnosis between the lowest and the highest polygenic risk quartiles. Conclusion Targeting screening to men at higher polygenic risk would reduce the problem of overdiagnosis in prostate cancer. Citation Format: Nora Pashayan, Stephen W. Duffy, David E. Neal, Freddie Hamdy, Jenny Donovan, Richard M. Martin, Patricia Harrington, Sara Benlloch, Ali A. Al Olama, Mitul Shah, Zsofia Kote-Jarai, Douglas F. Easton, Rosalind Eeles, Paul D. Pharoah. Implications of polygenic risk-stratified screening for prostate cancer on overdiagnosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 261. doi:10.1158/1538-7445.AM2014-261

Training recruiters to randomized trials to facilitate recruitment and informed consent by exploring patients' treatment preferences.

BackgroundPatients’ treatment preferences are often cited as barriers to recruitment in randomized controlled trials (RCTs). We investigated how RCT recruiters reacted to patients’ treatment preferences and identified key strategies to improve informed decision-making and trial recruitment.MethodsAudio-recordings of 103 RCT recruitment appointments with 96 participants in three UK multicenter pragmatic RCTs were analyzed using content and thematic analysis. Recruiters’ responses to expressed treatment preferences were assessed in one RCT (ProtecT - Prostate testing for cancer and Treatment) in which training on exploring preferences had been given, and compared with two other RCTs where this specific training had not been given.ResultsRecruiters elicited treatment preferences similarly in all RCTs but responses to expressed preferences differed substantially. In the ProtecT RCT, patients’ preferences were not accepted at face value but were explored and discussed at length in three key ways: eliciting and acknowledging the preference rationale, balancing treatment views, and emphasizing the need to keep an open mind and consider all treatments. By exploring preferences, recruiters enabled participants to become clearer about whether their views were robust enough to be sustained or were sufficiently weak that participation in the RCT became possible. Conversely, in the other RCTs, treatment preferences were often readily accepted without further discussion or understanding the reasoning behind them, suggesting that patients were not given the opportunity to fully consider all treatments and trial participation.ConclusionsRecruiters can be trained to elicit and address patients’ treatment preferences, enabling those who may not have considered trial participation to do so. Without specific guidance, some RCT recruiters are likely to accept initial preferences at face value, missing opportunities to promote more informed decision-making. Training interventions for recruiters that incorporate key strategies to manage treatment preferences, as in the ProtecT study, are required to facilitate recruitment and informed consent.Trial registrationProtecT RCT: Current Controlled Trials ISRCTN20141297. The other two trials are registered but have asked to be anonymized.

Psychological Impact of Prostate Biopsy: Physical Symptoms, Anxiety, and Depression

To investigate the psychological impact of prostate biopsy, including relationships between physical biopsy-related symptoms and anxiety and depression. A prospective cohort of 1,147 men, nested within the Prostate Testing for Cancer and Treatment trial and recommended to receive prostate biopsy, completed questionnaires assessing physical and psychological harms after biopsy in the Prostate Biopsy Effects study. Psychological impact was measured using the Hospital Anxiety and Depression Scale, and scores were compared according to experiences of biopsy-related symptoms at biopsy, and at 7 and 35 days afterward, and in relation to biopsy results. A total of 1,144 men (99.7%) returned questionnaires at biopsy, with 1,090 (95.0%) and 1,016 (88.6%) responding at 7 and 35 days postbiopsy. Most men experienced biopsy-related symptoms as no problem or a minor problem, and overall levels of anxiety and depression were low and similar to normative levels. Of men receiving a negative biopsy result (n = 471), anxiety was greater in those experiencing problematic biopsy-related symptoms compared with those experiencing nonproblematic symptoms at 7 days for the following symptoms: pain (P < .001), shivers, (P = .020), hematuria (P < .001), hematochezia (P < .001), and hemoejaculate (P < .001). Anxiety was reduced, although symptoms were not, after 35 days. Overall levels of anxiety were low across all time points except at the 35-day assessment among men who had received a cancer diagnosis. Problematic postbiopsy symptoms can lead to increased anxiety, distinct from distress related to diagnosis of prostate cancer. Men and doctors need to consider these additional potential harms of biopsy when deciding whether to initiate prostate-specific antigen testing.

Men with prostate cancer make positive dietary changes following diagnosis and treatment

Few studies have measured dietary changes made among men diagnosed with prostate cancer (PC) without formal dietary interventions, yet they may offer insight into the needs of PC survivors. This study examined dietary changes in men before and after treatment for PC within the prostate testing for cancer and treatment randomized trial. This was a prospective cohort study in community-based men aged 50-69 tested for PC in nine UK areas. 3,935 men completed food frequency questionnaires before diagnosis and 678 with localized PC repeated the questionnaire 1 year later (response 82.7 %). Men subsequently diagnosed with or without PC all consumed similar diets before diagnosis. Diagnosis of PC led to dietary changes, with 234 (34.7 %) men eating more fresh tomatoes (p < 0.0001) and 156 (23.5 %) more tomato products (p = 0.01). 271 (40.0 %) men consumed more protein (p < 0.0001) and 193 (28.6 %) more fruit/vegetable juice (p < 0.0001). Fewer macronutrients were obtained from dairy products (p < 0.01). Men undergoing active monitoring increased their fruit/vegetable juice intake after diagnosis (p = 0.0023) more than men who had surgery or radiotherapy. Around one-third of men spontaneously adopted a healthier diet and also consumed more 'prostate-healthy' foods following a diagnosis of PC. Dietary choices also differed by radical or monitoring treatments, indicating that men undergoing active surveillance may be more likely to pursue dietary changes as an adjunct therapy. PC survivors can adopt healthier diets, thus providing clinicians with opportunities to support PC survivorship by providing targeted advice beneficial to general and potentially prostate-specific health.

Very low PSA concentrations and deletions of the KLK3 gene.

Prostate-specific antigen (PSA), a widely used biomarker for prostate cancer (PCa), is encoded by a kallikrein gene (KLK3, kallikrein-related peptidase 3). Serum PSA concentrations vary in the population, with PCa patients generally showing higher PSA concentrations than control individuals, although a small proportion of individuals in the population display very low PSA concentrations. We hypothesized that very low PSA concentrations might reflect gene-inactivating mutations in KLK3 that lead to abnormally reduced gene expression. We have sequenced all KLK3 exons and the promoter and searched for gross deletions or duplications in KLK3 in the 30 individuals with the lowest observed PSA concentrations in a sample of approximately 85 000 men from the Prostate Testing for Cancer and Treatment (ProtecT) study. The ProtecT study examines a community-based population of men from across the UK with little prior PSA testing. We observed no stop codons or frameshift mutations, but we did find 30 single-base genetic variants, including 3 variants not described previously. These variants included missense variants that could be functionally inactivating and splicing variants. At this stage, however, we cannot confidently conclude whether these variants markedly lower PSA concentration or activity. More importantly, we identified 3 individuals with different large heterozygous deletions that encompass all KLK3 exons. The absence of a functional copy of KLK3 in these individuals is consistent with their reduced serum PSA concentrations. The clinical interpretation of the PSA test for individuals with KLK3 gene inactivation could lead to false-negative PSA findings used for screening, diagnosis, or monitoring of PCa.

Presenting Treatment Options to Men with Clinically Localized Prostate Cancer: The Acceptability of Active Surveillance/Monitoring

Presenting treatment options to men with localized prostate cancer is difficult because of the lack of definitive evidence and the range of treatment options available. Active surveillance and monitoring programs are now a recognized treatment option for men with low-risk localized prostate cancer, but many patients are not fully aware of the details of such programs, and most still opt for immediate radical (surgery or radiotherapy) treatment. The provision of high-quality information with decision aids has been shown to increase the acceptability of active surveillance/monitoring programs. This chapter outlines techniques for providing high-quality information about active surveillance/monitoring, based on the findings of a randomized controlled trial of treatments for localized prostate cancer. The ProtecT (Prostate testing for cancer and Treatment) trial has randomized over 1500 men between active monitoring, radical surgery, and radical radiotherapy by ensuring that information was tailored to men's existing knowledge and views. Care was taken with the content, order, and enthusiasm of the presentation of treatments by recruitment staff, and clinicians and other health professionals were supported to feel comfortable with being open about the uncertainties in the evidence and helped to rephrase terminology likely to be misinterpreted by patients. These techniques of information provision should be added to the use of decision aids to enable patients diagnosed with clinically localized prostate cancer in routine practice to reach well-informed and reasoned decisions about their treatment, including full consideration of active surveillance and monitoring programs.

PS05 Men With Prostate Cancer Make Positive Dietary Changes Following Treatment in a Randomised Trial: A Prospective Cohort Study

BackgroundProstate cancer (PC) is the second most frequently diagnosed cancer of men worldwide. A healthy diet may improve clinical outcomes but there is currently no disease-specific dietary advice available to...

Associations of circulating retinol, vitamin E, and 1,25-dihydroxyvitamin D with prostate cancer diagnosis, stage, and grade

Some epidemiological studies suggest that vitamin A (retinol), vitamin E, and vitamin D (total 25-hydroxyvitamin D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)(2)D) are protective against prostate cancer. However, the evidence is not conclusive, with positive and null associations reported for all three vitamins. Limitations of previous studies include small sample size, lack of population controls, and reliance on self-reported dietary intake. Few studies have explored the interactions of circulating 25(OH)D with 1,25(OH)(2)D or retinol, which are biologically plausible interactions. We investigated the associations of circulating retinol, vitamin E, and 1,25(OH)(2)D with PSA-detected prostate cancer risk, stage, and grade in a case-control study nested within the Prostate Testing for Cancer and Treatment (ProtecT) trial. We investigated the possibility of an interaction between 25(OH)D and 1,25(OH)(2)D and whether the previously observed association between 25(OH)D and prostate cancer may be modified by retinol levels. We included 1,433 prostate cancer cases and 1,433 healthy controls. There was no evidence of associations of circulating retinol, vitamin E, or 1,25(OH)(2)D with overall prostate cancer risk, stage (advanced vs localized), or Gleason grade (high- (≥7) vs low (<7) grade). There was no evidence of an interaction of 1,25(OH)(2)D and 25(OH)D with prostate cancer risk, stage, or grade (p interaction ≥ 0.24). The association between 25(OH)D and prostate cancer did not differ by retinol level (p interaction = 0.34). We found no evidence that retinol, vitamin E, or 1,25(OH)(2)D concentrations were associated with overall prostate cancer risk or more aggressive prostate cancer phenotypes. There was no evidence of an interaction between 25(OH)D and 1,25(OH)(2)D or retinol.

Predictors of 25-hydroxyvitamin D and its association with risk factors for prostate cancer: evidence from the Prostate testing for cancer and Treatment study

Circulating 25-hydroxyvitamin D (25(OH)D) may protect against prostate and other cancers. Few epidemiology studies have measured 25(OH)D on all participants, weakening the evidence-base through reduced statistical power and the potential for bias. We developed a score to predict individual 25(OH)D based on potential predictors, including sun exposure, nutrient intake, and vitamin D pathway genes, providing a method of substituting missing values. We assessed the usefulness of predicted 25(OH)D by comparison with multiple imputation of 25(OH)D levels. Amongst 1,091 controls from a population-based case-control study (ProtecT), we quantified relationships of sun exposure, demographic, clinical, anthropologic, nutrient, and genetic data with circulating 25(OH)D and constructed several prediction scores from subsets of these measures. We investigated associations of three prostate cancer risk factors (PSA level, BMI, family history of prostate cancer) with 25(OH)D levels in sensitivity analyses based upon participants with measured 25(OH)D only and based upon the addition of all participants with missing 25(OH)D levels substituted by prediction score values or by multiple imputation. Our score accounted for 27.7% of the variation in measured 25(OH)D. Associations with risk factors of prostate cancer were consistent across the different estimates of 25(OH)D. However, standard deviations for the prediction score did not incorporate extra error from prediction. Multiple imputation of missing 25(OH)D values predicted a more realistic range of 25(OH)D. In epidemiological studies of cancer risk associated with vitamin D, multiple imputation of missing 25(OH)D is preferable to prediction scores, as a wider range of 25(OH)D levels are imputed and appropriate confidence intervals calculated.

Short term outcomes of prostate biopsy in men tested for cancer by prostate specific antigen: prospective evaluation within ProtecT study

Objectives To measure the effect of the adverse events within 35 days of transrectal ultrasound guided biopsy from the perspective of asymptomatic men having prostate specific antigen (PSA) testing; to...

Associations of circulating 25‐hydroxyvitamin D with prostate cancer diagnosis, stage and grade

Epidemiological studies suggest that vitamin D protects against prostate cancer, although evidence is limited and inconsistent. We investigated associations of circulating total 25-hydroxyvitamin D (25(OH)D) with prostate specific antigen-detected prostate cancer in a case-control study nested within the prostate testing for cancer and treatment (ProtecT) trial. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) quantifying the association between circulating total 25(OH)D and prostate cancer. In case-only analyses, we used unconditional logistic regression to quantify associations of total 25(OH)D with stage (advanced vs. localized) and Gleason grade (high-grade (≥7) vs. low-grade (<7)). Predetermined categories of total 25(OH)D were defined as: high: ≥30 ng/mL; adequate: 20-<30 ng/mL; insufficient: 12-<20 ng/mL; deficient: <12 ng/mL. Fractional polynomials were used to investigate the existence of any U-shaped relationship. We included 1,447 prostate cancer cases (153 advanced, 469 high-grade) and 1,449 healthy controls. There was evidence that men deficient in vitamin D had a 2-fold increased risk of advanced versus localized cancer (OR for deficient vs. adequate total 25(OH)D=2.33, 95% CI: 1.26, 4.28) and high-grade versus low-grade cancer (OR for deficient vs. adequate total 25(OH)D=1.78, 95% CI: 1.15, 2.77). There was no evidence of a linear association between total 25(OH)D and prostate cancer (p=0.44) or of an increased risk of prostate cancer with high and low vitamin D levels. Our study provides evidence that lower 25(OH)D concentrations were associated with more aggressive cancers (advanced versus localized cancers and high- versus low-Gleason grade), but there was no evidence of an association with overall prostate cancer risk.

Qualitative research in evidence-based medicine: Improving decision-making and participation in randomized controlled trials of cancer treatments

Background: Since the 1990s there has been increasing emphasis on ‘evidence-based medicine’. The randomized controlled trial is widely regarded as the ‘gold-standard’ study design for evaluating interventions. However, placing too strong an emphasis on a phase III trial, to the neglect of earlier development and piloting work, may result in weaker interventions that are more difficult to evaluate and less likely to be implemented. Aim: To illustrate the benefits and outcomes of qualitative research at the early stages of the research continuum. Setting/Participants: Two cancer studies are evaluated in which the best treatment option is uncertain: ASPECTS (A Study of Patients ExperienCes of TreatmentS) and ProtecT (Prostate Testing for Cancer and Treatment). Design: To examine decision-making in relation to palliative chemotherapy for advanced cancer, ASPECTS was a qualitative study involving non-participant observation and recording of oncology consultations. During the ProtecT feasibility study, recruitment interviews were routinely audiotaped and in-depth interviews conducted with men to explore their understanding of treatment options and randomization to trial arms. Results: ASPECTS identified that insufficient information was given to patients about the survival benefits of palliative chemotherapy with implications for informed consent. ProtecT illustrated the effective use of qualitative research methods to resolve recruitment and randomization problems for a randomized controlled trial. Conclusions: These studies illustrate the value of qualitative research, particularly during the earlier phases of the research continuum. Such research may generate hypotheses, strengthen the development and implementation of interventions and enhance their evaluation: all of which are essential to evidence-based medicine.

Abstract 2782: Genetic susceptibility to prostate cancer progression and relationship with PSA level: Case-case study

Abstract Purpose: Prostate cancer is a mixture of progressive and non-progressive cancers. To date, genome-wide association studies have identified more than 30 common susceptibility variants associated with the risk of prostate cancer. However, case-control study designs have failed to identify variants consistently associated with aggressive cancer. The aim of this study is to investigate whether prostate cancer susceptibility variants distinguish between progressive and non-progressive cancers, using case-case study design. Methods: We genotyped 85 prostate cancer susceptibility variants in 4,856 men with prostate cancer identified from the Prostate Testing for Cancer and Treatment (ProtecT), Prostate Cancer Mechanisms of Progression and Treatment (ProMPT), and Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) studies. Men with advanced stage (T3-T4) (n=624), or Gleason score ≥ 7 (n=1,792) prostate cancer were compared to those with localised stage (T1-T2) (n=3,805), or Gleason score &amp;lt;7 (n=2,090) cancer, respectively, using logistic regression to estimate the odds ratio (OR) associated with risk allele and genotype, after controlling for age at diagnosis, PSA level at diagnosis, stage and / or Gleason score. Results: On univariate analysis, three variants (rs16901979, rs10896449, rs2735839) were associated with stage, and six (rs1447295, rs16901979, rs10896449, rs2735839 rs17181356 rs3760511) with Gleason score. In multivariate analysis, the variant rs2735839 at 19q13 in KLK2/3 region was associated with 42% increase in the odds for advanced stage cancer (adjusted OR per allele =1.42; 95% CI 1.08-1.87; ptrend =0.01). However, there was evidence of interaction with PSA level (p&amp;lt;0.001). The adjusted OR for rs2735839 for advanced compared to localised cancers among those with PSA ≥10ng/ml was 1.79 (95% CI 1.26-2.54; p=0.001), whereas among those with PSA&amp;lt;10ng/ml, the OR was 0.96 (95% CI 0.60-1.56; p=0.88). Whereas the variant rs3760511 at 17q12 was associated with reduced risk for high Gleason score cancer (adjusted OR per allele=0.85 95% CI 0.75-0.96; ptrend =0.01). Conclusion: The interaction between PSA level and stage may inform the underlying biological mechanism for cancer progression in stage. These findings may also have clinical utility in identifying tumours with and without the potential for progression to advanced stage or higher Gleason score. Further validation in larger studies would be needed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2782. doi:10.1158/1538-7445.AM2011-2782

Key issues in recruitment to randomised controlled trials with very different interventions: a qualitative investigation of recruitment to the SPARE trial (CRUK/07/011)

BackgroundRecruitment to randomised controlled trials (RCTs) with very different treatment arms is often difficult. The ProtecT (Prostate testing for cancer and Treatment) study successfully used qualitative research methods to improve recruitment and these methods were replicated in five other RCTs facing recruitment difficulties. A similar qualitative recruitment investigation was undertaken in the SPARE (Selective bladder Preservation Against Radical Excision) feasibility study to explore reasons for low recruitment and attempt to improve recruitment rates by implementing changes suggested by qualitative findings.MethodsIn Phase I of the investigation, reasons for low levels of recruitment were explored through content analysis of RCT documents, thematic analysis of interviews with trial staff and recruiters, and conversation analysis of audio-recordings of recruitment appointments. Findings were presented to the trial management group and a plan of action was agreed. In Phase II, changes to design and conduct were implemented, with training and feedback provided for recruitment staff.ResultsFive key challenges to trial recruitment were identified in Phase I: (a) Investigators and recruiters had considerable difficulty articulating the trial design in simple terms; (b) The recruitment pathway was complicated, involving staff across different specialties/centres and communication often broke down; (c) Recruiters inadvertently used 'loaded' terminology such as 'gold standard' in study information, leading to unbalanced presentation; (d) Fewer eligible patients were identified than had been anticipated; (e) Strong treatment preferences were expressed by potential participants and trial staff in some centres. In Phase II, study information (patient information sheet and flowchart) was simplified, the recruitment pathway was focused around lead recruiters, and training sessions and 'tips' were provided for recruiters. Issues of patient eligibility were insurmountable, however, and the independent Trial Steering Committee advised closure of the SPARE trial in February 2010.ConclusionsThe qualitative investigation identified the key aspects of trial design and conduct that were hindering recruitment, and a plan of action that was acceptable to trial investigators and recruiters was implemented. Qualitative investigations can thus be used to elucidate challenges to recruitment in trials with very different treatment arms, but require sufficient time to be undertaken successfully.Trial RegistrationCRUK/07/011; ISRCTN61126465

PSA‐detected prostate cancer and the potential for dedifferentiation—estimating the proportion capable of progression

The aims were to determine whether prostate-specific antigen (PSA)-detected prostate cancers progress to higher Gleason score during the preclinical screen-detectable phase, and, if so, to estimate the proportion of tumours with progressive potential. We developed two multi-state Markov chain models to represent the natural history of two tumour populations, one with (Model I) and the other without (Model II) the potential for progression. For each, we derived the transition rates between the states and used these estimates to calculate the expected prevalence of preclinical low and intermediate-to-high Gleason score prostate cancers, using data from the Prostate Testing for Cancer and Treatment (ProtecT) study on 2,310 prostate cancers detected by PSA testing in 71,511 men 50-69 years. We compared the expected prevalence for each tumour population to that of the observed based on ProtecT and the European Randomised Study on Screening for Prostate Cancer (ERSPC)-Rotterdam Centre's first round screening data, the latter allowing independent assessment of the two models. The overall expected proportion of low Gleason score tumours was 0.56 under Model I and 0.81 under Model II, whereas the observed proportion based on either ProtecT or ERSPC-Rotterdam was 0.69. Using the observed prevalence from ERSPC-Rotterdam, we estimated that 22, 33 and 66% of the tumours in men aged 55-59, 60-64 and 65-69 years, respectively, had the potential for progression in the preclinical phase. PSA-detected prostate cancers are a mixture of progressive and non-progressive tumours with respect to Gleason score. The former may potentially benefit from screening. Identifying cancers with the potential for progression is important to target screening.

Prostate cancer screening and treatment research

Screening for prostate cancer is not UK policy due to possible over diagnosis and over treatment of low risk disease. The ProtecT (Prostate testing for cancer and Treatment) RCT is evaluating active monitoring, radiotherapy and radical prostatectomy treatments for localised prostate cancer. The Comparison Arm for ProtecT (CAP) cluster randomised controlled trial compares the outcomes for about 450,000 men randomised to either provide prostate specific antigen testing (intervention) or standard clinical care.