Prespecified 4-Kallikrein Marker Model at Age 50 or 60 for Early Detection of Lethal Prostate Cancer in a Large Population Based Cohort of Asymptomatic Men Followed for 20 Years
This article is commented on by the following:
A prespecified statistical model based on 4 kallikrein markers in blood, commercially available as the 4Kscore®, has been shown to accurately detect high grade (greater than Grade Group 2) prostate cancer in men with moderately elevated prostate specific antigen. We assessed whether the model predicted prostate cancer metastasis or death in men not subject to prostate specific antigen screening.
Materials and Methods:
The cohort includes 43,692 unscreened prostate cancer-free men from a Swedish population based cohort with low rates of prostate specific antigen screening (Västerbotten Intervention Project). Using cryopreserved blood collected at ages 50 and 60 years from men in this cohort we analyzed the association between prostate specific antigen and other kallikrein marker levels in blood and risk of prostate cancer metastasis or death.
There were 308 with metastases and 172 prostate cancer deaths. Baseline prostate specific antigen was strongly associated with 20-year risk of prostate cancer death (c-index at age 50, 0.859, 95% CI 0.799–0.916; age 60, 0.840, 95% CI 0.799–0.878). Men 60 years old with prostate specific antigen below median (less than 1.2 ng/ml) had 0.4% risk of prostate cancer death at 20 years. Among men with moderately elevated prostate specific antigen (2.0 ng/ml or greater) the 4Kscore markedly improved discrimination (c-index 0.767 vs 0.828 and 0.774 vs 0.862 in men age 50 and 60, respectively). Long-term risk of prostate cancer death or metastasis in men with low 4Kscores was very low.
Screening should focus on men in top prostate specific antigen quartile at age 60 years. Men with elevated prostate specific antigen but a low 4Kscore can safely be monitored with repeated blood markers in place of immediate biopsy.
- 1. : A 16-yr follow-up of the European Randomized study of Screening for Prostate Cancer. Eur Urol 2019; 76: 43. Google Scholar
- 2. : Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40-55 and long term risk of metastasis: case-control study. BMJ 2013; 346: f2023. Crossref, Medline, Google Scholar
- 3. : Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study. BMJ 2010; 341: c4521. Crossref, Medline, Google Scholar
- 4. : Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet 2014; 384: 2027. Google Scholar
- 5. : Lead times and overdetection due to prostate-specific antigen screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst 2003; 95: 868. Google Scholar
- 6. : Predicting high-grade cancer at ten-core prostate biopsy using four kallikrein markers measured in blood in the ProtecT study. J Natl Cancer Inst 2015; 107: djv095. Google Scholar
- 7. : Clinical performance of the 4Kscore test to predict high-grade prostate cancer at biopsy: a meta-analysis of US and European clinical validation study results. Rev Urol 2017; 19: 149. Google Scholar
- 8. : Improving the specificity of screening for lethal prostate cancer using prostate-specific antigen and a panel of kallikrein markers: a nested case-control study. Eur Urol 2015; 68: 207. Google Scholar
- 9. : The role of plasma microseminoprotein-beta in prostate cancer: an observational nested case-control and Mendelian randomization study in the European prospective investigation into cancer and nutrition. Ann Oncol 2019; 30: 983. Google Scholar
- 10. : Cardiovascular disease and diabetes in the Northern Sweden Health and Disease Study Cohort--evaluation of risk factors and their interactions. Scand J Public Health Suppl 2003; 61: 18. Google Scholar
- 11. : Capture rate and representativity of The National Prostate Cancer Register of Sweden. Acta Oncologica 2015; 54: 158. Google Scholar
- 12. : A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer. Eur Urol 2015; 68: 464. Google Scholar
- 13. : Baseline prostate-specific antigen levels in midlife predict lethal prostate cancer. J Clin Oncol 2016; 34: 2705. Google Scholar
- 14. : Empirical estimates of prostate cancer overdiagnosis by age and prostate-specific antigen. BMC Med 2014; 12: 26. Google Scholar
- 15. : Long-term prediction of prostate cancer up to 25 years before diagnosis of prostate cancer using prostate kallikreins measured at age 44 to 50 years. J Clin Oncol 2007; 25: 431. Google Scholar
- 16. : Prostate-specific antigen at or before age 50 as a predictor of advanced prostate cancer diagnosed up to 25 years later: a case-control study. BMC Med 2008; 6: 6. Google Scholar
- 17. : Twenty-year risk of prostate cancer death by midlife prostate-specific antigen and a panel of four kallikrein markers in a large population-based cohort of healthy men. Eur Urol 2018; 73: 941. Google Scholar
- 18. : Levels of beta-microseminoprotein in blood and risk of prostate cancer in multiple populations. J Natl Cancer Inst 2013; 105: 237. Google Scholar
- 19. : A four-kallikrein panel predicts high-grade cancer on biopsy: independent validation in a community cohort. Eur Urol 2016; 69: 505. Google Scholar
- 20. : Detection of high grade prostate cancer among PLCO participants using a prespecified 4-kallikrein marker panel. J Urol 2017; 197: 1041. Link, Google Scholar
- 21. : A four-kallikrein panel and beta-microseminoprotein in predicting high-grade prostate cancer on biopsy: an independent replication from the Finnish Section of the European Randomized Study of Screening for Prostate Cancer. Eur Urol Focus 2017; 5: 561. Google Scholar
- 22. : Baseline prostate-specific antigen level in midlife and aggressive prostate cancer in black men. Eur Urol 2019; 75: 399. Google Scholar
- 23. : A multi-institutional prospective trial in the Veterans Affairs health system confirms the 4Kscore maintains its predictive value among African American men. J Urol 2018; 199: 1459. Link, Google Scholar
Presented at annual meeting of American Urological Association, San Francisco, California, May 18-21, 2018.
Supported by the National Institutes of Health/National Cancer Institute (NIH/NCI) with a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center (P30 CA008748), a SPORE grant in Prostate Cancer to Dr. H. Scher (P50-CA92629), an R01 grant to Dr. R. Klein (R01 CA175491), the Sidney Kimmel Center for Prostate and Urologic Cancers, David H. Koch through the Prostate Cancer Foundation. Also supported in part by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Program in the U.K., the Västerbotten County Council, the Swedish Cancer Society (CAN 2017/559), the Swedish Research Council (VR-MH project no. 2016-02974) and General Hospital in Malmö Foundation for Combating Cancer.
A full data set along with the statistical code used for analysis are available from the authors on request. These data can be used only for replication of the analyses published in this paper. Express written permission must be sought from the authors for any other data use.
No direct or indirect commercial, personal, academic, political, religious or ethical incentive is associated with publishing this article.
Supplementary materials are available at https://figshare.com/articles/Supplementary_Materials_Vertosick_et_al_docx/11935770.