Evaluating a polygenic hazard score to predict risk of developing metastatic or fatal prostate cancer in the multi-ancestry Million Veteran Program cohort

Importance: Early detection of prostate cancer to reduce mortality remains controversial because there is often also overdiagnosis of low-risk disease and unnecessary treatment. Genetic scores may provide an objective measure of a man's risk of dying from prostate cancer and thus inform screening decisions, especially in men of African ancestry, who have a higher average risk of prostate cancer death but are often treated as a homogeneous group. Objective: Determine whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with risk of metastatic or fatal prostate cancer in a racially and ethnically diverse population. Design: Million Veteran Program (MVP) cohort study, 2011-2021. Setting: Nation-wide study of United States military veterans. Participants: Population-based volunteer sample of male participants. Exposure(s): Genotype data were used to calculate the genetic score, PHS290. Family history of prostate cancer and ancestry group (harmonized genetic ancestry and self-reported race/ethnicity: European, African, Hispanic, or Asian) were also studied. Main Outcome(s) and Measure(s): Study designed after MVP data collected. Primary outcome: age at death from prostate cancer. Key secondary outcome: age at diagnosis of prostate cancer metastases. Hypothesis: A germline genetic score (PHS290) is associated with risk of fatal (or metastatic) prostate cancer. Results: 513,997 MVP participants were included. Median age at last follow-up: 69 years. PHS290 was associated with age at death from prostate cancer in the full cohort and for each ancestry group (p<1e-16). Comparing men in the highest 20% of PHS290 to those in the lowest 20%, the hazard ratio for death from prostate cancer was 4.41 [95% CI: 3.9-5.02]. Corresponding hazard ratios for European, African, Hispanic, and Asian subsets were 4.26 [3.66-4.9], 2.4 [1.77-3.23], 4.72 [2.68-8.87], and 10.46 [2.01-101.0]. When accounting for family history and ancestry group, PHS290 remained a strong independent predictor of fatal prostate cancer. PHS290 was also associated with metastasis. PHS290 was higher, on average, among men with African ancestry. Conclusions and Relevance: PHS290 stratified US veterans of diverse ancestry for lifetime risk of metastatic or fatal prostate cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.

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649: Prostate Cancer Screening in Persons with a Positive Family History

The Journal of Urology ◽

10.1016/s0022-5347(18)37911-4 ◽

2004 ◽

Vol 171 (4S) ◽

pp. 172-173

Author(s):

Kathleen Herkommer ◽

Juergen E. Gschwend ◽

Martina Kron ◽

Richard E. Hautmann ◽

Thomas Paiss

Keyword(s):

Prostate Cancer ◽

Cancer Screening ◽

Family History ◽

Prostate Cancer Screening ◽

Positive Family History

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Prostate Cancer

10.1093/oso/9780190676827.003.0020 ◽

2018 ◽

Author(s):

Kathryn M. Wilson ◽

Lorelei Mucci

Keyword(s):

Prostate Cancer ◽

Risk Factors ◽

Family History ◽

Prostate Specific Antigen ◽

Advanced Prostate Cancer ◽

Advanced Disease ◽

African Ancestry ◽

Specific Antigen ◽

Dietary Factors ◽

Increased Risk

Prostate cancer is among the most commonly diagnosed cancers among men, ranking second in cancer globally and first in Western countries. There are marked variations in incidence globally, and its incidence must be interpreted in the context of diagnostic intensity and screening. The uptake of prostate-specific antigen screening since the 1990s has led to dramatic increases in incidence in many countries, resulting in an increased proportion of indolent cancers that would never have come to light clinically in the absence of screening. Risk factors differ when studying prostate cancer overall versus advanced disease. Older age, African ancestry, and family history are established risk factors for prostate cancer. Obesity and smoking are not associated with risk overall, but are associated with increased risk of advanced prostate cancer. Several additional lifestyle factors, medications, and dietary factors are now emerging as risk factors for advanced disease.

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Prostate cancer screening characteristics in men with BRCA1/2 mutations attending a high-risk prevention clinic

Canadian Urological Association Journal ◽

10.5489/cuaj.1970 ◽

2014 ◽

Vol 8 (11-12) ◽

pp. 783 ◽

Cited By ~ 3

Author(s):

Richard Walker ◽

Alyssa Louis ◽

Alejandro Berlin ◽

Sheri Horsburgh ◽

Robert G. Bristow ◽

...

Keyword(s):

Prostate Cancer ◽

Family History ◽

High Risk ◽

Prostate Cancer Screening ◽

Brca2 Mutation ◽

Aggressive Disease ◽

Mutation Carriers ◽

The Family ◽

History Of ◽

Prevention Clinic

Introduction: The prostate-specific antigen (PSA) era and resultant early detection of prostate cancer has presented clinicians with the challenge of distinguishing indolent from aggressive tumours. Mutations in the BRCA1/2 genes have been associated with prostate cancer risk and prognosis. We describe the prostate cancer screening characteristics of BRCA1/2 mutation carriers, who may be classified as genetically-defined high risk, as compared to another high-risk cohort of men with a family history of prostate cancer to evaluate the utility of a targeted screening approach for these men.Methods: We reviewed patient demographics, clinical screening characteristics, pathological features, and treatment outcomes between a group of BRCA1 or BRCA2 mutation carriers and age-matched men with a family history of prostate cancer followed at our institutional Prostate Cancer Prevention Clinic from 1995 to 2012.Results: Screening characteristics were similar between the mutation carriers (n = 53) and the family history group (n = 53). Some cancers would be missed in both groups by using a PSA cut-off of >4 ug/L. While cancer detection was higher in the family history group (21% vs. 15%), the mutation carrier group was more likely to have intermediate- or high-risk disease (88% vs. 36%). BRCA2 mutation carriers were more likely to have aggressive disease, biological recurrence, and distant metastasis.Conclusions: In our cohort, regular screening appears justified for detecting prostate cancer in BRCA1 and BRCA2 carriers and other high-risk populations. Lowering PSA cut-offs and defining monitoring of PSA velocity as part of the screening protocol may be useful. BRCA2 is associated with more aggressive disease, while the outcome for BRCA1 mutation carriers requires further study. Large multinational studies will be important to define screening techniques for this unique high-risk population.

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Family History and Risk of Fatal Prostate Cancer

Epidemiology ◽

10.1097/00001648-199711000-00011 ◽

1997 ◽

Vol 8 (6) ◽

pp. 653-657 ◽

Cited By ~ 34

Author(s):

Carmen Rodríguez ◽

Eugenia E. Calle ◽

Heidi L. Miracle-McMahill ◽

Lilith M. Tatham ◽

Phyllis A. Wingo ◽

...

Keyword(s):

Prostate Cancer ◽

Family History ◽

Fatal Prostate Cancer

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Personal prostate-specific antigen screening and treatment choices for localized prostate cancer among expert physicians

Canadian Urological Association Journal ◽

10.5489/cuaj.4736 ◽

2017 ◽

Vol 12 (2) ◽

pp. E59-63

Author(s):

Christopher Wallis ◽

Douglas Cheung ◽

Laurence Klotz ◽

Venu Chalasani ◽

Ricardo Leao ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Screening ◽

Prostate Cancer Screening ◽

Specific Antigen ◽

Secondary Outcome ◽

University Of Toronto ◽

Radiation Oncologists ◽

Medical Oncologists ◽

Treat Prostate Cancer ◽

Healthcare Interventions

Introduction: We aimed to determine the personal practices of urologists, radiation oncologists, and medical oncologists regarding prostate cancer screening and treatment using the physician surrogate method, which seeks to identify acceptable healthcare interventions by ascertaining interventions physicians select for themselves.Methods: A hierarchical, contingent survey was developed through a consensus involving urologists, medical oncologists, and radiation oncologists. It was piloted at the University of Toronto and then circulated to urologists, radiation oncologists, and medical oncologists through professional medical societies in the U.S., Canada, Central and South America, Australia, and New Zealand. The primary outcome was physicians’ personal choices regarding prostatespecific antigen (PSA) screening and the secondary outcome was treatment selection among those diagnosed with prostate cancer.Results: A total of 869 respondents provided consent and completed the survey. Of these, there were 719 urologists, 89 radiation oncologists, nine medical oncologists, and 53 undisclosed specialists. Most (784 of 869 respondents; 90%) endorsed past or future screening for themselves (among male physicians) or for relatives (among female physicians). Among urologists and radiation oncologists making prostate cancer treatment decisions, there was a significant correlation between physician specialty and the treatment selected (Phi coefficient=0.61; p=0.001).Conclusions: Physicians who routinely treat prostate cancer are likely to undertake prostate cancer screening themselves or recommend it for immediate family members. Treatment choice is influenced by the well-recognized specialty bias.

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Evolving Recommendations on Prostate Cancer Screening

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_157413 ◽

2016 ◽

pp. e80-e87

Author(s):

Otis W. Brawley ◽

Ian M. Thompson ◽

Henrik Grönberg

Keyword(s):

Prostate Cancer ◽

Family History ◽

New Technologies ◽

Prostate Cancer Screening ◽

Large Population ◽

Specific Antigen ◽

Population Based ◽

Low Grade ◽

Diagnostic Study ◽

High Grade

Results of a number of studies demonstrate that the serum prostate-specific antigen (PSA) in and of itself is an inadequate screening test. Today, one of the most pressing questions in prostate cancer medicine is how can screening be honed to identify those who have life-threatening disease and need aggressive treatment. A number of efforts are underway. One such effort is the assessment of men in the landmark Prostate Cancer Prevention Trial that has led to a prostate cancer risk calculator (PCPTRC), which is available online. PCPTRC version 2.0 predicts the probability of the diagnosis of no cancer, low-grade cancer, or high-grade cancer when variables such as PSA, age, race, family history, and physical findings are input. Modern biomarker development promises to provide tests with fewer false positives and improved ability to find high-grade cancers. Stockholm III (STHLM3) is a prospective, population-based, paired, screen-positive, prostate cancer diagnostic study assessing a combination of plasma protein biomarkers along with age, family history, previous biopsy, and prostate examination for prediction of prostate cancer. Multiparametric MRI incorporates anatomic and functional imaging to better characterize and predict future behavior of tumors within the prostate. After diagnosis of cancer, several genomic tests promise to better distinguish the cancers that need treatment versus those that need observation. Although the new technologies are promising, there is an urgent need for evaluation of these new tests in high-quality, large population-based studies. Until these technologies are proven, most professional organizations have evolved to a recommendation of informed or shared decision making in which there is a discussion between the doctor and patient.

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