One in six men with biopsy-determined grade group 1 (GG1) prostate cancer has non-low-risk disease when clinical data are also considered, putting them at increased risk for prostate cancer-specific mortality, show data from a population-based study led by researchers at Weill Cornell Medicine.
“The results highlight that within the current diagnostic paradigm, biopsy histology alone does not adequately capture long-term prognosis because [prostate cancer-specific mortality] significantly increases across risk groups,” write Neal Patel, MD, urologic oncologist at Weill Cornell Medicine and New York-Presbyterian, and co-authors in JAMA Oncology. “Therefore, terminology and communication with patients regarding the malignant potential of GG1 [prostate cancer] on biopsy must be contextualized along with other disease characteristics within validated and supported risk-stratification schema.”
The researchers explain that there is currently controversy surrounding whether GG1 prostate cancer should have a cancer label. Advocates for redesignating GG1 as a noncancerous entity argue that so-called pure GG1 disease, determined after radical prostatectomy rather than biopsy, does not metastasize, and diagnostic tools, such as magnetic resonance imaging and genomic biomarkers, have reduced the risk of missing higher-grade cancers on diagnosis.
However, prostate cancer guidelines do not recommend management decisions based on biopsy histology alone but rather in conjunction with clinical risk parameters such as stage, disease volume, and prostate-specific antigen level.
“There is a misunderstanding that ‘low grade’ and ‘low risk’ are the same. Here, we show clearly that they are not,” said co-senior author Jonathan Shoag, MD, associate professor of urology at Case Western Reserve University and urologist at University Hospitals Cleveland. “Attempts to rename GG1 are misguided as many patients with GG1 cancers on biopsy have substantial risks of their cancers causing pain and suffering over their lifetime if untreated.”
He explained: “There has been an unfortunate conflation of several different terms by some of my colleagues who are trying to rename GG1 cancer. One is that biopsy GG1 and prostatectomy GG1 are similar, but they are not. As clinicians, we must make decisions based on each patient and his biopsy results in that context.”
The researchers analyzed cancer-specific outcomes in 117,162 men (median age 64 years) with localized GG1 prostate cancer who were registered in the Surveillance, Epidemiology, and End Results Prostate With Watchful Waiting database.
The men were stratified into four groups according to National Comprehensive Cancer Network prostate cancer risk categories, which consider tumor stage, grade, and PSA level. The majority (84.5%) were low risk but 8.9% had favorable intermediate-risk disease, 2.7% had unfavorable intermediate-risk disease, and 3.9% had high-risk disease.
Among the participants who underwent radical prostatectomy, 15.8% of 26,452 men with low-risk GG1 prostate cancer had adverse pathology, compared with 22.4% of 2478 men with favorable intermediate-risk, 31.2% of 1246 men with unfavorable intermediate-risk, and 59.6% of 1455 men with high-risk GG1 prostate cancer.
Statistical analyses, adjusted for potential confounders, showed that men with favorable intermediate-risk GG1 prostate cancer were a significant 1.42 times more likely to have adverse pathology than those with low-risk prostate cancer, while the odds were a significant 2.31-fold and 7.15-fold higher for men with unfavorable intermediate-risk and high-risk GG1 prostate cancer, respectively.
The researchers also showed that the risk for prostate cancer specific mortality was significantly higher in men with favorable intermediate-risk GG1, unfavorable intermediate-risk GG1, and high-risk GG1, at hazard ratios of 1.60, 2.10, and 3.58, respectively.
Of note, the 10-year cumulative prostate cancer specific mortality rates for unfavorable intermediate-risk GG1 and for high-risk GG1, at 2.4% and 4.7%, respectively, were comparable to the prostate cancer–specific mortality rates for those observed among individuals with favorable intermediate-risk GG2 and unfavorable intermediate-risk greater than or equal to GG2, which were 2.1% and 4.0%, respectively.
Patel told Inside Precision Medicine that the increased risk for prostate cancer specific mortality among men with non-low risk GG1 prostate cancer highlights the “need to better understand this group of men to determine how they should be managed.” They are usually followed through active surveillance but some need additional treatment such as radiotherapy or radical prostatectomy.
Neal suggests that precision medicine tools such as liquid biopsies or tumor genomics could help better determine which men would benefit from treatment and which are suitable for active surveillance. “The current risk stratification paradigm and prostate MRI are very helpful but still have limitations,” he said.
He also stresses that although some men are at increased risk for poor outcomes, active surveillance is still suitable for most men with GG1 prostate cancer. “We strongly believe that active surveillance is the appropriate treatment for the majority of men with GG1 prostate cancer and the utilization still needs to increase for men with low risk GG1,” he said. “Clinically however we often see patients with GG1 on biopsy but adverse clinical features (such as high PSA) that make us hesitant to place them on surveillance. Future studies on this subset are needed to best determine how they should be treated.”
In addition, Al Hussein, MD, sees room for improving how patients are counseled. “We need to find a better way to inform patients about their prognosis when they have GG1 prostate cancer with adverse clinical features,” he said. “As physicians, the responsibility falls on us to educate patients and provide them with the information they need to understand their diagnosis and decide on the best approach for treatment, while continuing to advocate for active surveillance for those who are indeed low risk.”
