Prostate Cancer In Canada Research Articles

Connecting with prostate cancer survivors

It is that time of year again when men around the world will begin to sport a moustache (with many of their significant others patiently showing solidarity) in support for men’s health issues and, more specifically, prostate cancer. The Movember campaign is an enigma that has blossomed over the decade; last year it raised 41 million dollars in Canada. Through its word-of-mouth campaign, backstopped by viral social media exposure, Movember has quickly become one of the most effective forces in prostate cancer advocacy, demonstrating a public voice that many of our professional organizations have difficulty achieving. The subsequent fundraising has facilitated infrastructure development and substantial research funding with a global perspective.1 Over a similar period, there has been a shift in our understanding of prostate cancer biology and even its definition, with significant downstream implications on diagnosis and treatment paradigms. The substantial focus on technology adoption and comparative efficacy of treatments for localized disease is a fascinating foil to the outcomes of the large randomized trials that have informed us on the potential harms of PSA screening and over-treatment of low-risk disease. This has culminated in the USPSTF recommendation on PSA screening earlier this year and fueled scrutiny and, arguably, healthy debate on the management of prostate cancer in most advanced nations. Leung and colleagues highlights yet another concern central to this conversation – the ability of clinicians to effectively identify men with sufficient life expectancy to benefit from the early diagnosis and intervention.2 These results are perhaps not surprising in the face of previous reports suggesting that almost 10% of men treated in Ontario die of other causes within 10 years of definitive treatment of their disease.3 The “layers of uncertainty” 4 that have resulted from this knowledge gap have complicated our ability to communicate and support our patients, especially those who are considering PSA testing or contemplating their preferred management for localized disease. This underscores the need to re-double our efforts to create, study and implement effective health communication for the benefit of men and their families, and not lose site of some of the gains realized over the years. This is no less true for those men with advancing disease given the complexity arising from the multiplicity of new and emerging therapies for castration resistant prostate cancer. Prostate Cancer Canada, funded by the Movember Foundation, has announced the establishment of “A Survivorship Action Partnership” (ASAP), a multidisciplinary collaborative network that draws on healthcare professionals from various settings to help improve the lives of prostate cancer survivors, their partners and family members across Canada. ASAP aims to create strategies that will positively impact clinical practice and create supportive environments to increase self-management and improve the quality of life of men facing a diagnosis of prostate cancer. Undoubtedly this will require up-to-date, comprehensive and widely applicable solutions to effective health communication and informed treatment decision-making. This is perhaps a tall order given the rapidly changing landscape that is prostate cancer, but such endeavors do need to be lauded.

Abstract 1970: Liposomal nanoparticle siRNA delivery systems for in vivo silencing of the androgen receptor in human prostate cancer

Abstract Prostate cancer is the most commonly diagnosed non-skin cancer in men and one of the leading causes of cancer-death. While frequently curable by surgical or radiation ablation, recurrent or metastatic disease is usually managed with androgen withdrawal therapies (medical castration), which block the growth promoting effects of androgens on the androgen receptor (AR). Unfortunately, the cancers eventually progress to the lethal castration-resistant state. Previously, we reported that knocking down the AR by RNA interference using small hairpin RNA (shRNA) inhibits this progression and, in about 50% of tumours, causes complete regression. In this study, we investigated the ability of small interfering RNA (siRNA) encapsulated in lipid nanoparticle (LNP) to silence AR in human prostate cancer cell lines and xenograft tumours following intravenous injections. In vitro screening studies with prostate cancer cell lines using a panel of cationic lipids demonstrated that siRNA formulated in LNPs containing the ionizable cationic lipid 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA) exhibited the most potent AR silencing effects. This is attributed to an optimized ability of DLin-KC2-DMA-containing LNP to enter into cells and to release the siRNA into the cell cytoplasm following endocytotic uptake. DLin-KC2-DMA LNPs were also effective in silencing the AR in a wild-type AR expressing cell line, LAPC-4, and a variant AR expressing cell line, CWR22Rv1. Importantly, we found that LNP AR-siRNA systems containing DLin-KC2-DMA could silence AR gene expression in distal LNCaP xenograft tumors and decrease serum PSA levels following intravenous injection. The 5′RACE experiments further confirmed that siRNA-induced specific cleavage of AR mRNA was the primary mechanism of action. In conclusion, these results indicate that in vivo delivery of siRNA to knockdown AR using our LNP formulations causes a decrease in serum PSA and provides proof in principle that this approach may offer a therapeutic strategy for treating advanced prostate cancer. (Funded by Canadian Institutes for Health Research and a PCF-STAR Project from Prostate Cancer Canada with the support of Safeway Canada) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1970. doi:1538-7445.AM2012-1970

Abstract 3184: Whole genome sequencing of low-input fresh frozen prostate cancer biopsies

Abstract Prostate cancer is the most commonly diagnosed malignancy among men in the United States. Due to an aging population, prostate cancer incidence has been increasing, with an estimated 200,000 men being diagnosed in 2010 and more than 32,000 deaths resulting from this disease. Better predictors of patient prognosis and treatment outcome are required to individualize prostate cancer treatment. High-throughput genomic sequence-based approaches offer a unique opportunity to identify biomarkers of disease-progression, thereby enabling more individualized therapy. The Canadian Prostate Cancer Genome Network (CPC-GENE) is an outcomes-based initiative that will sequence 500 specimens from 350 prostate cancer patients over a 5-year time span. Previously, whole genome sequencing efforts from biopsy specimens have been hindered by insufficient quantities of extracted DNA required as input for sequencing library construction. As a proof of concept to demonstrate the ability to sequence low input amounts of DNA from prostate biopsies, whole genome sequencing has been initiated for 50 prostate tumor biopsy samples along with their matched blood-derived reference sample. An on-bead sample preparation protocol was optimized using decreasing quantities of input DNA and used to construct sequencing libraries from as low as 100ng of DNA derived from macrodissected fresh frozen prostate biopsies (>70% cellularity). Sequencing is performed on the Illumina HiSeq 2000 platform to generate coverage depths of 50x for tumor samples and 30x for reference samples. Following alignment using NovoAlign and variant-calling using GATK, we compared our results to genotyping-array results generated using the Affymetrix OncoScan platform. Single-nucleotide variants detected using arrays were validated >99% of the time by sequence data, confirming that the use of a low-input library did not hinder mutation detection. Sequencing does not exhibit significant genome-wide coverage biases, and CNV calls were compared between the genotyping arrays and the next-generation sequencing data. Outcomes from the sequencing and analysis of the initial 50 sample sets will similarly be applied over a 5-year period to characterize an additional 450 prostate specimens. The ability to whole genome sequence specimens where minimal amounts of extracted DNA exist presents new opportunities to sequence many samples previously deemed unusable, while also providing encouraging prospects for whole genome sequencing applications for future studies using biopsy specimens. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3184. doi:1538-7445.AM2012-3184

A Call to Arms: moving forward from “Fostering the Partnership” Canadian GU Cancers Survivorship Conference 2011

Fostering the Partnership was a unique and innovative forum for genitourinary (GU) cancer survivors, advocacy groups and health care professionals (HCPs) to explore ways to collaboratively enhance GU cancer survivorship. The idea evolved from the growing recognition that new models of care are required to: (a) meet the diverse needs of an increasingly active and informed patient population; (b) respond to the desire of cancer survivors to give back; and (c) leverage their growing skill set as expert patients and potential research collaborators. The event, endorsed by the Canadian Urological Association, the Canadian Uro-Oncology Group and the Urology Nurses of Canada, and supported by industry partners, was held on January 19–20, 2011 in King City, Ontario. Forty-three individuals attended: 18 cancer survivors/caregivers, 22 HCPs and 3 researchers representing bladder, kidney, prostate and testicular cancers, clinical subspecialties and GU patient advocacy groups, including Bladder Cancer Canada, Kidney Cancer Canada, Prostate Cancer Canada and the Canadian Testicular Cancer Association. The event was an overwhelming success. Evaluations showed that 99% of attendees were extremely pleased with the event and would like to hold another. The following were identified as priorities. Meeting participants would like the Canadian GU community to recognize them as important future initiatives. Review current strategies and best practices that foster partnerships between cancer survivors and HCPs. Assess the knowledge of HCPs regarding the needs of GU cancer survivors, existing advocacy groups/community support organizations and their services, as well as barriers and facilitators for promoting active partnerships with cancer survivors. Establish priorities for GU cancer survivorship research with collaborative input from and participation by GU cancer survivors and HCPs. Facilitate direct communication, knowledge exchange and collaboration between GU cancer survivor advocacy groups and the HCPs. Facilitate networking, collaborative programming and fundraising among GU cancer survivor advocacy groups. Define the ideal patient journey for each GU cancer type, identify gaps in current services, and disseminate tools (e.g., Survivorship Care Plan/ Passport to Health) to facilitate improvement in these areas. Synthesize up-to-date information about GU cancer survivor advocacy groups/community support organizations and their services in an easy-to-access, web-based format for HCPs and cancer survivors. Facilitate ongoing opportunities for peer-to-peer support, community building and networking among GU cancer survivors throughout the cancer journey. Hold a follow-up conference led collaboratively by GU cancer survivors and HCPs based on the recommendations of this report. This is our “Call to Arms” to you, our colleagues. It is time to embrace survivorship in our practices and address these priorities. A complete description of the event, its recommendations and strategies to accomplish them is forthcoming.

Use of genetic instability to predict biochemical recurrence in intermediate-risk prostate cancer.

42 Background: Biomarkers of local and systemic recurrence are needed to individualize patient risk categories and better define treatment. We hypothesized that genomic instability, as measured by percent genome alteration (PGA), can predict for biochemical failure in intermediate- risk prostate cancer. Methods: High-resolution array comparative genomic hybridization (arrayCGH) was used to identify PGA in frozen biopsies from 120 intermediate-risk prostate cancer patients. Our cohort included 39 T1c tumors, 78 T2 tumors and 2 T3 tumors. The Gleason score was 6 in 32 tumors, 7 in 82 tumors and 8–9 in 6 tumors. PSA ranged from 2.1–33 (median 8.0). Patients were treated with intensity-modulated radiotherapy (IMRT) with doses of 75.6–79.8 Gy in 1.8–2Gy fractions, or 60–66 Gy in 3 Gy fractions.. Twenty-five percent of patients also received neoadjuvant-concurrent bicalutamide (150mg po od). Biochemical failure, defined by Phoenix criteria or the initiation of salvage therapy, was observed in 35 patients after median follow-up of 5.4 years (range 0.9–8.8). Results: Array CGH showed variable PGA ranging from <1% to 35% (median 6.7%). PSA and the use of hormonal therapy independently influenced biochemical relapse, and formed a baseline clinical model to which PGA was added. PGA was found to be a strong predictor of biochemical relapse (p<0.0001) independent of the clinical prognostic factors (pre-treatment PSA, Gleason score and T-category). PGA was also found to be associated with unique tumour suppressor and oncogene gene loci clusters involved in genetic stability (e.g. loss of PTEN, p53, RB, NKX3.1, ATM, PARP-1 and gain of c-MYC; validated by in situ FISH). Conclusions: This is the first report to show genetic instability can independently predict for biochemical recurrence in intermediate-risk prostate cancer. Current studies are associating specific gene loci regions with clinical outcome. Our results could provide a way forward for individualized medicine for non-indolent prostate cancer based on initial daignostic biopsy material. Supported by Prostate Cancer Canada, The Terry Fox Foundation and the Canadian Cancer Society. No significant financial relationships to disclose.

The Changing Age Distribution of Prostate Cancer in Canada

Prostate cancer incidence rates are still increasing steadily; mortality rates are levelling, possibly decreasing; and hospitalization rates for many diagnoses are decreasing. Our objective is to examine changes in age distributions of prostate cancer during these times of change. Prostate cancer cases were derived from the Canadian Cancer Registry, prostate cancer deaths from Vital Statistics, hospitalizations from the Hospital Morbidity File. Age-standardized rates were calculated based on the 1991 Canadian population. A prevalence correction for incidence rates was calculated. Age-specific incidence rates increased until 1995 for all ages, but a superimposed peak (1991-94) was greatest between ages 60-79. After 1995, increases in incidence continued for the under-70 age groups. Prevalence correction indicated the greatest underestimation of incidence rates for the oldest ages, but was less in Canada than in the United States. Mortality rates increased until 1994, then levelled and slowly decreased; age-specific mortality rates showed the greatest increase for the oldest ages but the earliest downturn for younger age groups. While hospitalizations dropped drastically after 1991, this drop was confined to elderly men (70+). Dramatic changes in age distributions of prostate cancer incidence, mortality and hospitalizations altered age profiles of men with prostate cancer. This illustrated the changing nature of prostate cancer as a public health issue and has important implications for health care provision, e.g., the increased numbers of younger new patients have different needs from the increasing numbers of elderly long-term patients who now spend less time in hospital.

Lifetime and Recent Prostate Specific Antigen (PSA) Screening of Men for Prostate Cancer in Canada

In spite of national guidelines which do not recommend prostate specific antigen (PSA) screening for prostate cancer or are inconclusive, Canadian men may be accessing the screening test. For the purpose of informing prostate screening policy, cross-sectional self-reported data from the Canadian Community Health Survey (2000-2001) were analyzed to determine the lifetime and recent PSA screening prevalence of Canadian men aged 50 and older with no prostate cancer, and to explore the socio-demographic characteristics associated with ever being screened. Multivariate binomial regression analyses were used to calculate prevalence rate ratios as a measure of association between respondents' characteristics and PSA screening behaviour. Almost half of Canadian men over the age of 50 years (47.5%; 95% CI=46.4-48.5) reported receiving PSA screening during their lifetime. Seventy-two percent (71.8%) of PSA screening was performed within one year prior to the survey or recently. Lifetime prevalence was highest among men aged 60-69 (53.1%; 95% CI=51.1-55.1). Next to advanced age, having a family doctor was the most predictive of screening behaviour (PRR=1.83, p<0.01). Black ethnicity, a risk factor for prostate cancer, failed to be predictive of screening (PRR=1.04, NS). Not speaking French or English was strongly associated with not obtaining a PSA screen (PRR=0.66, p< or =0.01). Our finding that Canadian men commonly reported PSA screening for prostate cancer is not congruent with national guidelines. While we wait for randomized controlled trial evidence of the effectiveness of PSA screening in reducing mortality due to prostate cancer, PSA screening has emerged as a public health issue.

Survival Patterns for the Top Four Cancers in Canada: The Effects of Age, Region and Period

This study examined the variations in survival rates (1989-1991) and the trends (1969-1991), by sex, age and province, for patients diagnosed with breast, colorectal, lung or prostate cancer in Canada and compared the Canadian rates with those of nine American SEER registries. Five-year age-standardized relative survival rates (ASRs) were calculated, and the trends were estimated from variance-weighted linear regression of the ASRs for five periods of diagnosis (1969-1973, 1974-1978, 1979-1983, 1984-1988 and 1989-1991). In 1989-1991, the ASR varied among provinces for each cancer except female colorectal cancer. The lowest survival rates were observed in the youngest patients (15-44) for breast and prostate cancers, and in the oldest patients (75-99) of both sexes for lung and colorectal cancers. Over the five periods, a major trend toward improved survival was observed for breast, prostate and colorectal cancers (P<0.008), whereas no changes were seen for lung cancer. The ASRs in the western region were higher than in the Atlantic region over time (P<0.02) for each cancer. From the third period onward, the ASRs for Canadian patients with lung cancer were similar to those for the US patients and lower than for Canadian patients with breast, prostate or colorectal cancer. The observed increases in ASR for breast and prostate cancer are likely due to the increased use of screenings and the improved treatment modalities.

Survival patterns for the top four cancers in Canada: the effects of age, region and period

This study examined the variations in survival rates (1989-1991) and the trends (1969-1991), by sex, age and province, for patients diagnosed with breast, colorectal, lung or prostate cancer in Canada and compared the Canadian rates with those of nine American SEER registries. Five-year age-standardized relative survival rates (ASRs) were calculated, and the trends were estimated from variance-weighted linear regression of the ASRs for five periods of diagnosis (1969-1973, 1974-1978, 1979-1983, 1984-1988 and 1989-1991). In 1989-1991, the ASR varied among provinces for each cancer except female colorectal cancer. The lowest survival rates were observed in the youngest patients (15-44) for breast and prostate cancers, and in the oldest patients (75-99) of both sexes for lung and colorectal cancers. Over the five periods, a major trend toward improved survival was observed for breast, prostate and colorectal cancers (P<0.008), whereas no changes were seen for lung cancer. The ASRs in the western region were higher than in the Atlantic region over time (P<0.02) for each cancer. From the third period onward, the ASRs for Canadian patients with lung cancer were similar to those for the US patients and lower than for Canadian patients with breast, prostate or colorectal cancer. The observed increases in ASR for breast and prostate cancer are likely due to the increased use of screenings and the improved treatment modalities.

Exisulind: Aptosyn, FGN 1, Prevatac, sulindac sulfone.

Exisulind: Aptosyn, FGN 1, Prevatac, sulindac sulfone.