Clinical and Genomic Characterization of Low-Prostate-specific Antigen, High-grade Prostate Cancer.
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 (pinteraction<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; pinteraction=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.
['Mahal|Brandon A|BA|', 'Yang|David D|DD|', 'Wang|Natalie Q|NQ|', 'Alshalalfa|Mohammed|M|', 'Davicioni|Elai|E|', 'Choeurng|Voleak|V|', 'Schaeffer|Edward M|EM|', 'Ross|Ashley E|AE|', 'Spratt|Daniel E|DE|', 'Den|Robert B|RB|', 'Martin|Neil E|NE|', 'Mouw|Kent W|KW|', 'Orio|Peter F|PF|', 'Choueiri|Toni K|TK|', 'Taplin|Mary-Ellen|ME|', 'Trinh|Quoc-Dien|QD|', 'Feng|Felix Y|FY|', 'Nguyen|Paul L|PL|']
D000368:Aged D014408:Biomarkers, Tumor D002423:Cause of Death D000066491:Clinical Decision-Making D016208:Databases, Factual D020022:Genetic Predisposition to Disease D006801:Humans D007610:Kallikreins D008297:Male D008875:Middle Aged D060787:Neoplasm Grading D009367:Neoplasm Staging D010641:Phenotype D011237:Predictive Value of Tests D017430:Prostate-Specific Antigen D011471:Prostatic Neoplasms D012189:Retrospective Studies D018570:Risk Assessment D012307:Risk Factors D018426:SEER Program D013997:Time Factors D014481:United States
Genomics Prostate cancer Prostate-specific antigen Androgen deprivation therapy Neuroendocrine Gleason score Small-cell cancer