Growing evidence indicates that more patients with favorable Grade Group 2 prostate cancer can be successfully managed with active surveillance and achieve acceptable oncologic outcomes, even if later treatment is required. For the past five years, a team of MSK researchers has been searching for better ways to characterize disease risk among Grade Group 2 patients on active surveillance.
“Our evidence indicates an increase in Gleason pattern 4 (GP4) may be a better trigger for moving to definitive treatment for men with Grade Group 2 prostate cancer monitored on active surveillance than the ratio of GP3 to GP4 disease,” said MSK urologic surgeon Behfar Ehdaie, MD, MPH, senior author of a study published recently in Clinical Genitourinary Cancer. (1) “This insight will help us deescalate treatment and expand active surveillance to more patients with intermediate-risk disease.”
Dr. Ehdaie and colleagues, including research methodologist Andrew Vickers, PhD, and genitourinary pathologist Samson Fine, MD, also previously published a study on integrating their findings with multiparametric magnetic resonance imaging (MRI) results in Cancer. (2) Additionally, Dr. Vickers, Dr, Ehdaie, and Dr. Fine are leading a global, multi-institutional initiative focused on creating and validating an open-source algorithm for further characterizing the quantification of GP4 disease in Grade Group 2 patients using artificial intelligence (AI).
Dr. Ehdaie, Dr. Vickers, and Dr. Fine are members of the MSK team which was ranked #1 in the nation for Urology Cancer Care this year by U.S. News & World Report.
“In addition to our extensive surgical expertise at MSK, we remain focused on determining which patients don’t need surgery or radiation and can continue on active surveillance, with a view to maximizing quality of life while maintaining excellent oncologic outcomes,” Dr. Ehdaie said. “MSK has one of the largest active surveillance programs for prostate cancer in the world, managing about 300 patients annually. Some patients have been in the program for more than 20 years of follow-up.”
GP4 Length: A Better Indicator of Aggressive Prostate Cancer
Intermediate-risk prostate cancer is heterogeneous: both Grade Group 2 and Grade Group 3 may contain a mix of GP3 and GP4 disease. Traditionally, pathological progression to Grade Group 3 on surveillance biopsy, as determined by the ratio of GP3 to GP4, has been a trigger for initiating treatment. However, using this ratio is problematic since an increase in relatively indolent GP3 can obscure an increase in more aggressive GP4 disease.
Various methods of quantifying GP4 have been proposed, including overall %GP4, maximal core %GP4, maximal GP4 core length (mm), and total GP4 length (mm). (3) (4)Previous work by MSK investigators demonstrated that the total length of GP4 was the most predictive of adverse pathology and oncologic outcomes after radical prostatectomy. (3) (5) Specifically, for men with 2 mm of GP4 on biopsy, the risk of adverse pathology was 45%, and the three-year biochemical recurrence (BCR) rate was 13%. Further, for each 1-mm increase in GP4, the risk of adverse pathology increased by 6% to 8%, and three-year BCR rates increased by 1% to 2%. (3) (5)
For their current study, Dr. Ehdaie and colleagues assessed data from 61 patients treated at MSK between November 2014 and March 2020 with Grade Group 2 disease on diagnostic and subsequent surveillance biopsy about one year later.
They found that some patients with significant increases in GP4 length had not met the criteria for a diagnosis of Grade Group 3 disease. Conversely, they also found an instance where a patient met the criteria for upgrading to Grade Group 3 despite a minimal change in GP4 length.
“Our results suggest that GP4 length, in addition to reclassification to Grade Group 3 disease, should be assessed in men with Grade Group 2 disease on active surveillance,” said Dr. Ehdaie. “We are now designing larger prospective studies to test this hypothesis.”
Incorporating MRI-Targeted Biopsy Results into Oncologic Risk
MSK and other large centers are increasingly using multiparametric MRI to aid in the diagnosis and monitoring of localized prostate cancer. (6) Well-controlled clinical trials have shown that high-Grade Group disease is rare in men with negative MRI and that MRI-targeted cores identify high-Grade Group tumors not detected by systematic prostate biopsy. (7) (8) (9)
However, questions remain about whether systematic and MRI-targeted biopsies are oncologically equivalent or whether the detection method influences cancer risk. The answer is critical since the National Comprehensive Cancer Network treatment guidelines were based on the pre-MRI era. For example, the guidelines recommend androgen deprivation therapy for men receiving radiotherapy for Grade Group 3, but not Grade Group 2 disease. (10) “This recommendation would not be required if more precise targeting and increased sampling were causing grade migration rather than biological oncologic risk,” said Dr. Ehdaie.
At MSK, men typically undergo both MRI-targeted and systematic prostate biopsy before radical prostatectomy. This allowed urologic surgeon Christopher Gaffney, MD, Dr. Ehdaie, and colleagues to compare the oncologic risk identified by each method. Their retrospective review of 991 patients treated at MSK revealed that when grades differed between the systematic biopsy and the MRI-targeted biopsy, the “true” risk of aggressive cancer was between the two grades.
“Only high-volume academic research centers that are leaders in prostate cancer, such as MSK, can perform a detailed level of quantification on every patient’s biopsy cores,” said Dr. Ehdaie.
MSK-Led AI Initiative for Characterizing Active-Surveillance-Monitored GP4 Disease
Dr. Ehdaie, Dr. Vickers, and Dr. Fine are leading a multi-institutional study at 16 centers worldwide focused on digitizing pathology slides for a large cohort of patients with prostate cancer monitored on active surveillance.
“What’s exciting about this initiative is that we are proposing to use AI to more deeply characterize GP4 disease, create an open-source algorithm for stratifying patient risk, and validate it in subsequent large cohorts of patients,” Dr. Ehdaie said. “The bottom line is that the Gleason grading system was established in 1968. While it has withstood the test of time with an unmatched ability to predict prostate cancer risk, we think there’s not only room for improvement, but it’s also long overdue, especially given that the natural history of GP3 disease is typically indolent, whereas GP4 is aggressive disease.”
The study published in Clinical Genitourinary Cancer was supported by funding from the Sidney Kimmel Center for Prostate and Urologic Cancers at MSK, the NIH/NCI SPORE in Prostate Cancer grant (P50 CA092629), and the NIH/NCI Cancer Center Support Grant to MSK (P30 CA008748). The paper published in Cancer was supported by the Patient-Centered Outcomes Research Institute grant (ME-2018C2-13253 and the same NIH/NCI grants as the first paper. Access disclosures for Dr. Ehdaie, Dr. Vickers, Dr. Fine, and Dr. Gaffney.