Risk factors for prostate cancer detection after a negative biopsy: a novel multivariable longitudinal approach

Abstract

Purpose: To introduce a novel approach for the time-dependent quantification of risk factors for prostate cancer (PCa) detection after an initial negative biopsy.

Patients and methods: Data for 1,871 men with initial negative biopsies and at least one follow-up biopsy were available. Piecewise exponential regression models were developed to quantify hazard ratios (HRs) and define cumulative incidence curves for PCa detection for subgroups with specific patterns of risk factors over time. Factors evaluated included age, race, serum prostate-specific antigen (PSA) concentration, PSA slope, digital rectal examination, dysplastic glands or prostatitis on biopsy, ultrasound gland volume, urinary symptoms, and number of negative biopsies.

Results: Four hundred sixty-five men had PCa detected, after a mean follow-up time of 2.8 years. All of the factors were independent predictors of PCa detection except for PSA slope, as a result of its correlation with time-dependent PSA level, and race. PSA (HR = 3.90 for > 10 v 2.5 to 3.9 ng/mL), high-grade prostatic intraepithelial neoplasia/atypical glands (HR = 2.97), gland volume (HR = 0.39 for > 50 v < 25 mL), and number of repeat biopsies (HR = 0.36 for two v zero repeat biopsies) were the strongest predictors. Men with high-risk versus low-risk event histories had a 20-fold difference in PCa detection over 5 years.

Conclusion: Piecewise exponential models provide an approach to longitudinal analysis of PCa risk that allows clinicians to see the interplay of risk factors as they unfold over time for individual patients. With these models, it is possible to identify distinct subpopulations with dramatically different needs for monitoring and repeat biopsy.

Fig 1.

Hazard ratios and 95% CIs for risk of prostate cancer after an initial negative biopsy—right-censored model (n = 1,871). (*) Number of months from first study visit to initial biopsy (baseline date for this analysis). (†) Binary variable to indicate change in May 1995 in minimum number of biopsy cores (four to six cores) and prostate-specific antigen (PSA) threshold for biopsy (4.0 to 2.5 ng/mL). DRE, digital rectal examination; CA, cancer; HGPIN, high-grade prostatic intraepithelial neoplasia; TRUS, transrectal ultrasound.

Fig 2.

Cumulative incidence of prostate cancer with varying (A) age; (B) digital rectal examination (DRE), gland volume, and urinary symptoms (Sx); (C) prostate-specific antigen (PSA); and (D) number of negative biopsies. Each graph includes a basic event history curve shown with a blue line and alternative histories are shown with gold, gray, and red lines. All covariates not mentioned are set to reference levels as in Table 2. Note the small effect of age and DRE relative to PSA and gland volume and that for men with persistent PSA of 7 to 10 ng/mL, risk remains elevated after several negative biopsies.

Fig 3.

Cumulative incidence curves for prostate cancer detection among men less than age 55 years with prostate-specific antigen (PSA) of 4 to 7 ng/mL at baseline. Each graph includes a basic event history curve shown with a blue line and alternative histories shown with gold and gray lines. All covariates not mentioned are set to reference levels as in Table 2. High-grade prostatic intraepithelial neoplasia (HGPIN)/atypical glands on initial biopsy increases cumulative risk by approximately 40% at 4 years. A PSA increase at 12 months adds a small amount of additional risk; however, absolute risk is already asymptotically approaching 100%.

Fig 4.

Cumulative incidence curves for prostate cancer detection among men age 55 to 60 years with high- or low-risk event histories. High risk is defined as gland volume less than 25 mL, prostate-specific antigen (PSA) increasing from 4 to 7 ng/mL to more than 10 ng/mL at 12 months, and high-grade prostatic intraepithelial neoplasia/atypical glands at baseline. Low risk is defined as gland volume more than 50 mL, PSA of 2.5 to 4 ng/mL and steady, prostatitis on initial biopsy, and negative biopsies at 6 and 12 months.