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Eur Urol. 2018 Aug;74(2):146-154. doi: 10.1016/j.eururo.2018.01.043. Epub 2018 Feb 22.

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

Author information

1
Harvard Radiation Oncology Program, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
2
Harvard Medical School, Boston, MA, USA.
3
GenomeDx Biosciences, Vancouver, British Columbia, Canada.
4
Department of Urology, Northwestern University, Chicago, IL, USA.
5
James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
6
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
7
Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA.
8
Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, MA, USA.
9
Harvard Medical School, Boston, MA, USA; Department of Medical Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, MA, USA.
10
Harvard Medical School, Boston, MA, USA; Division of Urological Surgery, Brigham and Women's Hospital, Boston, MA, USA.
11
Departments of Radiation Oncology, Urology, and Medicine and Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA.
12
Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: pnguyen@lroc.harvard.edu.

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 (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.

KEYWORDS:

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

PMID:
29478736
PMCID:
PMC6615042
DOI:
10.1016/j.eururo.2018.01.043
[Indexed for MEDLINE]
Free PMC Article

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