Improving detection and reducing overtreatment of prostate cancer

Prostate cancer is a global health issue being the second most common cancer in men. In Sweden, prostate cancer is the most common cancer in men with one in five Swedish men receiving the diagnosis in their lifetime. The blood biomarker PSA has revolutionized the diagnosis and monitoring of prostate cancer. Unfortunately, PSA is not specific for prostate cancer and has led to overdiagnosis and overtreatment of low-risk cancers. Active surveillance has emerged as an alternative to active treatment of low-risk disease. The guidelines for active surveillance are constantly evolving with emerging research findings.

In Study I, we investigated which clinical variables are associated with adverse pathology (ISUP 3 or higher and/or a pathological T-stage of T3 or higher) after radical prostatectomy in a cohort of men initially diagnosed with low-risk prostate cancer and enrolled in active surveillance between 2008 and 2017 in Stockholm County, Sweden. Our results showed that 37.7% of men had adverse pathology at radical prostatectomy. Clinical T-stage and PSA at diagnoses in addition to age, PSA, and PI-RADS on MRI at last re-biopsy were statistically significantly associated with adverse pathology, supporting guidelines incorporating PSA and MRI in active surveillance protocols.

The association between use of 5-alpha reductase inhibitors for benign prostate hyperplasia and prostate cancer has long been debated, with most studies showing a decreased incidence, particularly of low-risk prostate cancer. However, studies investigating the association between 5-ARI and prostate cancer mortality have shown more disparate results. Study II evaluated the association between 5-ARI and prostate cancer mortality and all-cause mortality using a population-based cohort study design including 429,977 men in Stockholm, Sweden between 2007 and 2018. Cox proportional hazards regression models were used to compute adjusted hazard ratios. There were 35,767 deaths during follow-up, with 852 deaths attributable to prostate cancer. Longer exposure times were associated with a decreased risk of prostate cancer mortality (0.1-2.0 years: HR, 0.89; 95% CI, 0.64- 1.25; >8 years: HR, 0.44; 95% CI, 0.27-0.74). No association between 5-ARI and all-cause mortality was found, regardless of exposure time. The study suggests that use of 5-ARIs are safe regarding prostate cancer mortality and may decrease the risk, however, it remains unknown if the differences are due to inherent medication properties.

Most current clinical guidelines suggest incorporating MRI in the diagnostic chain of prostate cancer after an elevated PSA test. Studies have shown its efficacy in reducing the number of biopsies, overdiagnosis of low-risk disease, and improved detection of clinically significant cancer. However, MRI is still a bottleneck in many healthcare settings with demand exceeding supply. The Stockholm3 test is clinical prediction model of clinically significant prostate cancer incorporating clinical variables, PSA, and a polygenic risk score. Study III compared the detection of clinically significant prostate cancer between two screening pathways: PSA + Stockholm3 + Systematic biopsies and PSA + MRI + Systematic and targeted biopsies. The study was performed within the STHLM3MRI prostate cancer screening randomized clinical trial. Our results showed that the Stockholm3 test with systematic biopsies can detect clinically significant prostate cancer at similar rates as PSA with MRI and systematic/targeted biopsies. However, the Stockholm3 pathway required more biopsies (6.3% vs. 4.4%) and detected more indolent disease cases (1.2% vs. 0.5%), suggesting the approach may be suitable in settings with limited MRI resources.

PSA density is more specific for clinically significant prostate cancer compared to PSA alone. In Study IV, we investigated if PSA density could be used as a selection tool for undergoing MRI in men with an elevated PSA. The study took place within the experimental arm of the STHLM3MRI trial. The results showed that a PSA density cutoff of 0.075 mg/ml2 would miss only 5% of clincally significant prostate cancers while reducing the number of MRIs by 28%. However, at a PSA density cutoff of 0.15 mg/ml2, nearly half (44%) of clinically significant prostate cancers would be missed with a 78% reduction in the number of MRIs. The results suggest that PSA density could be used to select men for MRI, however, lower cutoffs than typically recommended in guidelines should be used.

In conclusion, the overaching aim of this thesis was to improve detection of prostate cancer as well as reducing overdiagnosis and overtreatment. In addition, a commonly used medication was assessed in regards to its safety concerning prostate cancer mortality.

List of scientific papers

I. Björnebo, L., Olsson, H., Nordström, T., Jäderling, F., Grönberg, H., Eklund, M., Lantz, A.
Predictors of adverse pathology on radical prostatectomy specimen in men initially enrolled in active surveillance for low-risk prostate cancer. World Journal of Urology, 2021, 39, 1797-1804 https://doi.org/10.1007/s00345-020-03394-7

II. Björnebo, L., Nordström, T., Discacciati, A., Palsdottir, T., Aly, M., Grönberg, H., Eklund, M., Lantz, A.
Association of 5a-reductase inhibitors with prostate cancer mortality. JAMA Oncology, 2022, 8.7, 1019-26 https://doi.org/10.1001/jamaoncol.2022.1501

III. Björnebo, L., Discacciati, A., Falagario, U., Vigneswaran, H.T., Jäderling, F., Grönberg, H., Eklund, M., Nordström, T., Lantz, A.
Biomarker vs MRI-Enhanced Strategies for Prostate Cancer Screening: The STHLM3-MRI Randomized Clinical Trial. JAMA Network Open, 2024, 7.4, e247131-e247131 https://doi.org/10.1001/jamanetworkopen.2024.7131

IV. Björnebo, L., Discacciati, A., Chandra Engel, J., Falagario, U., Abbadi, A., Vigneswaran, H.T., Jäderling, F., Grönberg, H., Eklund, M., Lantz, A, Nordström, T.
PSA Density as a Selection Tool before MRI in Prostate Cancer Screening: an Analysis from the STHLM3MRI Trial. [Manuscript]