Clinical and Genomic Characterization of Low-Prostate-specific Antigen, High-grade Prostate Cancer

Abstract

Background: The consequences of low prostate-specific antigen (PSA) in high-grade (Gleason 8-10) prostate cancer are unknown.

Objective: To evaluate the clinical implications and genomic features of low-PSA, high-grade disease.

Design, setting, and participants: This was a retrospective study of clinical data for 494 793 patients from the National Cancer Data Base and 136 113 patients from the Surveillance, Epidemiology, and End Results program with cT1-4N0M0 prostate cancer (median follow-up 48.9 and 25.0 mo, respectively), and genomic data for 4960 patients from the Decipher Genomic Resource Information Database. Data were collected for 2004-2017.

Outcome measurements and statistical analysis: Multivariable Fine-Gray and Cox regressions were used to analyze prostate cancer-specific mortality (PCSM) and all-cause mortality, respectively.

Results and limitations: For Gleason 8-10 disease, using PSA 4.1-10.0ng/ml (n=38 719) as referent, the distribution of PCSM by PSA was U-shaped, with an adjusted hazard ratio (AHR) of 2.70 for PSA ≤2.5ng/ml (n=3862, p<0.001) versus 1.97, 1.36, and 2.56 for PSA of 2.6-4.0 (n=4199), 10.1-20.0 (n=17 372), and >20.0ng/ml (n=16 114), respectively. By contrast, the distribution of PCSM by PSA was linear for Gleason ≤7 (using PSA 4.1-10.0ng/ml as the referent, n=359 898), with an AHR of 0.41 (p=0.13) for PSA ≤2.5ng/ml (n=37 812) versus 1.38, 2.28, and 4.61 for PSA of 2.6-4.0 (n=54 152), 10.1-20.0 (n=63 319), and >20.0ng/ml (n=35 459), respectively (p_interaction<0.001). Gleason 8-10, PSA ≤2.5ng/ml disease had a significantly higher PCSM than standard high-risk/very high-risk disease with PSA >2.5ng/ml (AHR 2.15, p=0.002; 47-mo PCSM 14% vs 4.9%). Among Gleason 8-10 patients treated with radiotherapy, androgen deprivation therapy was associated with a survival benefit for PSA >2.5ng/ml (AHR 0.87; p<0.001) but not ≤2.5ng/ml (AHR 1.36; p=0.084; p_interaction=0.021). For Gleason 8-10 tumors, PSA ≤2.5ng/ml was associated with higher expression of neuroendocrine/small-cell markers compared to >2.5ng/ml (p=0.046), with no such relationship for Gleason ≤7 disease.

Conclusions: Low-PSA, high-grade prostate cancer has very high risk for PCSM, potentially responds poorly to androgen deprivation therapy, and is associated with neuroendocrine genomic features.

Patient summary: In this study, we found that low-prostate-specific antigen, high-grade prostate cancer has a very high risk for prostate cancer death, may not respond well to androgen deprivation therapy, and is associated with neuroendocrine genomic features. These findings suggest that current nomograms and treatment paradigms may need modification.

Keywords: Androgen deprivation therapy; Genomics; Gleason score; Neuroendocrine; Prostate cancer; Prostate-specific antigen; Small-cell cancer.

Fig. 1

PCSM in the SEER cohort. Adjusted hazard ratios with 95% confidence intervals and moving-average trend lines for the association between PSA and PCSM for (A) Gleason 8–10 and (B) Gleason ≤7 disease. Adjusted cumulative incidence of PCSM by National Comprehensive Cancer Network risk group compared to PSA ≤2.5 ng/ml, Gleason 8–10 disease (C). GS = Gleason score; HR/VHR = high risk/very high risk; IR, intermediate risk; LR/VLR = low risk/very low risk; PCSM = prostate cancer-specific mortality; PSA = prostate-specific antigen; SEER = Surveillance, Epidemiology and End Results.

Fig. 2

Adjusted Kaplan Meier curves of ACM for patients with Gleason 8–10 disease treated with definitive radiotherapy. (A) PSA >2.5 ng/ml and (B) PSA ≤2.5 ng/ml. Patients were identified from the National Cancer Data Base cohort. ACM = all-cause mortality; ADT = androgen deprivation therapy; PSA = prostate-specific antigen.

Fig. 3

Genomic characterization of patients from the Decipher GRID cohort. (A) Neuroendocrine/small-cell signature and (B) AR activity scores were the only prostate cancer signatures (among 62 signatures) that remained significantly associated with prostate-specific antigen groups after adjustment for multiple testing for Gleason 8–10 tumors, but did not remain significant for (C,D) Gleason ≤7 tumors. AR = androgen receptor; NE/SC = neuroendocrine/small-cell; PSA = prostate-specific antigen.