Patients with Gleason 8 to 10 prostate cancer (PCa) and PSA values of 2.5 ng/mL or less may harbor hormone-resistant disease that is more lethal than other forms of non-metastatic, node-negative prostate cancers, investigators reported at the American Society of Clinical Oncology (ASCO) Annual Meeting.

David D. Yang, BA, and colleagues of Harvard Medical School in Boston, characterized the prognosis of a low PSA in high-grade PCa based on data from more than a half-million men diagnosed with cT1-4 N0M0 PCa from the Surveillance, Epidemiology, and End Results (SEER) program 2010-2013 and the National Cancer Database (NCDB) 2004-2011. Of Gleason 8 to 10 tumors, 5.6% were diagnosed with PSA 2.5 ng/mL or less.

When the team analyzed PCa-specific mortality for Gleason 8 to 10 disease, the association between PSA and mortality appeared U-shaped, men who had a PSA level of 2.5 ng/mL or less exhibiting just as high mortality as those with a PSA level above 20.0 ng/mL. Likewise, in the months after they were diagnosed, patients with low-PSA, high-grade disease died at a rate much higher than patients deemed high- or very-high risk by National Comprehensive Cancer Network (NCCN) criteria (excluding those with PSA at or below 2.5 ng/mL). PCa-specific mortality was 2.15 times higher for low-PSA, high-grade PCa patients than this NCCN group. All-cause mortality results from NCDB demonstrated a similar relationship: Patients with low-PSA, high-grade disease had higher risks of dying than NCCN high-risk patients with higher PSA values. The risk of dying from any cause was 15% higher for low-PSA, high-grade PCa patients.

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Androgen deprivation therapy (ADT) might not improve survival of low-PSA, high-grade PCa, according to the investigators. For other men with Gleason 8 to 10 tumors treated with external beam radiation therapy, ADT appeared to increase survival: ADT was associated with 13% decreased risk of death from any cause when PSA values were above 2.5 ng/mL. For low-PSA, high-grade PCa patients, however, the risk of all-cause mortality increased by 36% with ADT. 

“Low PSA, high-grade prostate cancer appears to be a unique hormone-resistant entity with a high risk of prostate cancer-specific mortality that responds poorly to standard treatment,” Yang told Renal & Urology News.

He said their findings have two major clinical implications. First, existing clinical prognostic tools for PCa predicts a linear relationship between PSA and prognosis. “Yet, our results indicate that while this may be true for low-grade disease, it is inaccurate for high-grade disease and that patients with low PSA also have poor outcomes.”

Second, standard treatment for high-risk prostate cancer consists of radiation with long-course ADT. However, low-PSA, high-grade disease appears to be potentially resistant to hormone therapy.

“Given these results, a concerted effort in the community will be needed to help guide the development of prognostic tools, novel therapeutics, and clinical management of low-PSA, high-grade disease,” Yang said.

The investigators urged future research into the molecular classification of low-PSA, high-grade PCa to better understand the disease and determine optimal treatment.

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Yang DD, Mahal BAV, Sweeney C, Trinh QD, Feng FYC, Nguyen PL. Identification of low prostate-specific antigen, high Gleason prostate cancer as a unique hormone-resistant entity with poor survival: A contemporary analysis of 640,000 patients. 2017 ASCO Annual Meeting. J Clin Oncol 35, 2017 (suppl; abstr 5080). Poster 154.