Improving the Specificity of Screening for Lethal Prostate Cancer Using Prostate-specific Antigen and a Panel of Kallikrein Markers: A Nested Case-Control Study

Abstract

Background: A disadvantage of prostate-specific antigen (PSA) for the early detection of prostate cancer (PCa) is that many men must be screened, biopsied, and diagnosed to prevent one death.

Objective: To increase the specificity of screening for lethal PCa at an early stage.

Design, setting, and participants: We conducted a case-control study nested within a population-based cohort. PSA and three additional kallikreins were measured in cryopreserved blood from a population-based cohort in Västerbotten, Sweden. Of 40379 men providing blood at ages 40, 50, and 60 yr from 1986 to 2009, 12542 men were followed for >15 yr. From this cohort, the Swedish Cancer Registry identified 1423 incident PCa cases, 235 with distant metastasis.

Outcome measurements and statistical analysis: Risk of distant metastasis for different PSA levels and a prespecified statistical model based on the four kallikrein markers.

Results and limitations: Most metastatic cases occurred in men with PSA in the top quartile at age 50 yr (69%) or 60 yr (74%), whereas 20-yr risk of metastasis for men with PSA below median was low (≤0.6%). Among men with PSA >2 ng/ml, a prespecified model based on four kallikrein markers significantly enhanced the prediction of metastasis compared with PSA alone. About half of all men with PSA >2 ng/ml were defined as low risk by this model and had a ≤1% 15-yr risk of metastasis.

Conclusions: Screening at ages 50-60 yr should focus on men with PSA in the top quartile. A marker panel can aid biopsy decision making.

Patient summary: For men in their fifties, screening should focus on those in the top 10% to 25% of PSA values because the majority of subsequent cases of distant metastasis are found among these men. Testing of four kallikrein markers in men with an elevated PSA could aid biopsy decision making.

Keywords: Cancer metastasis; Kallikrein-related peptidases; Prostate biopsy; Prostate cancer; Prostate-specific antigen.

Fig. 1

Risk of distant metastasis within 15 yr (dashed line) and 20 yr (solid line) by prostate-specific antigen (PSA). The four areas depicted in dark and light gray reflect the four quartiles of the population distribution of PSA levels. (a) Age 60 yr; (b) age 50 yr. PSA = prostate-specific antigen.

Fig. 1

Risk of distant metastasis within 15 yr (dashed line) and 20 yr (solid line) by prostate-specific antigen (PSA). The four areas depicted in dark and light gray reflect the four quartiles of the population distribution of PSA levels. (a) Age 60 yr; (b) age 50 yr. PSA = prostate-specific antigen.

Fig. 2

Risk of distant metastasis among men with elevated prostate-specific antigen (PSA) by four kallikrein (KLK) panel score. (a) Age 60 yr and PSA ≥3 ng/ml (n = 2430). Black line: overall risk of distant metastasis; red line: risk of distant metastasis among men with four KLK panel score ≥7.5% (62% of the men); blue line: risk of distant metastasis among men with four KLK panel score <7.5% (38% of the men). (b) Age 50 yr and PSA ≥2 ng/ml (n = 1692). Black line: overall risk of distant metastasis; red line: risk of distant metastasis among men with four KLK panel score ≥5% (41% of the men); blue line: risk of distant metastasis among men with four KLK panel score <5% (59% of the men). PSA = prostate-specific antigen. -Insert space between PSA and symbol (eg, change PSA≥3 to PSA ≥3) -Change “Time from baseline, in years” to “Time from baseline, yr”

Fig. 2

Risk of distant metastasis among men with elevated prostate-specific antigen (PSA) by four kallikrein (KLK) panel score. (a) Age 60 yr and PSA ≥3 ng/ml (n = 2430). Black line: overall risk of distant metastasis; red line: risk of distant metastasis among men with four KLK panel score ≥7.5% (62% of the men); blue line: risk of distant metastasis among men with four KLK panel score <7.5% (38% of the men). (b) Age 50 yr and PSA ≥2 ng/ml (n = 1692). Black line: overall risk of distant metastasis; red line: risk of distant metastasis among men with four KLK panel score ≥5% (41% of the men); blue line: risk of distant metastasis among men with four KLK panel score <5% (59% of the men). PSA = prostate-specific antigen. -Insert space between PSA and symbol (eg, change PSA≥3 to PSA ≥3) -Change “Time from baseline, in years” to “Time from baseline, yr”