Integrated Diagnostics and Patient Selection for Active Surveillance Versus Immediate Treatment

By GU Oncology Now Editors - Last Updated: January 17, 2022

Current evidence for selection of newly-diagnosed prostate cancer patients for active surveillance using multiparametric prostate MRI (mpMRI) and genomic biomarkers was reviewed by Sanoj Punnen, MD, MAS, Pap Corps Champion for Cancer Research Endowed Chair in Solid Tumor Research, University of Miami, Miller School of Medicine and Sylvester Comprehensive Cancer Center.

Active surveillance has been traditionally used for men with low-grade tumors, applying stringent selection criteria due to concern about under-sampling on biopsy. Such criteria included low stage disease (<T2a), favorable Gleason scores (<7), less than two positive biopsy cores, or absolute initial prostate specific antigen values of less than 15 ng/ml. However, these criteria have broadened due to increasing acceptance of surveillance and long-term data showing its safety, but also due to the emergence of magnetic resonance imaging (MRI) and MRI-guided biopsies that provide more certainty about the true tumor grade and the extent of the tumor in the prostate. However, Dr. Punnen urged caution when incorporating this information into selection of patients for surveillance.

From experience at his own institution, Dr. Punnen described how, in 100 men eligible for active surveillance based on template biopsy (7 criteria), addition of MRI ultrasound fusion biopsy cores resulted in 10-40% of men becoming ineligible for active surveillance.1. “The majority of these patients had tumors that were unnecessarily removed from active surveillance, mainly because the MRI- guided biopsy found a little more low-grade cancer and over-selected for regions that were harboring the disease,” Dr. Punnen reported. Based on these advances, Dr. Punnen suggested that it might be time to re-evaluate traditional criteria for active surveillance in the era of multiparametric MRI (mpMRI)-guided prostate biopsy.2

Dr. Punnen noted that in the current National Comprehensive Cancer Network (NCCN) prostate cancer guidelines3 for very low, low, and intermediate risk patients, physicians are recommended to consider confirmatory prostate biopsy with or without mpMRI to confirm candidacy for active surveillance, rather than supporting their conclusive use in patient work-up. This ambivalence was illustrated by the ASIST trial, in which prostate cancer patients were randomized to 12-core systematic biopsy or MRI with systematic and targeted biopsy. Although initial results showed no difference in rates of reclassification between the two study arms,4 at 2-year follow-up, patients undergoing MRI guided prostate biopsy had a lower risk of progression or reclassification5 suggesting that MRI guided prostate biopsy is a better predictor of which patients are better candidates for active surveillance. Although the investigators attributed the 2-year findings to greater experience with MRI and biopsy, the study provided Level 1 evidence supporting MRI and MRI- targeted confirmatory biopsies in better selecting patients unlikely to progress on active surveillance.

Data on the role of MRI-targeted biopsy during monitoring is less clear, Dr Punnen acknowledged. A study by the National Institutes of Health compared standard systematic biopsy and MRI-targeted prostate biopsy in prostate cancer patients under active surveillance.6 At 2 years, MRI-targeted biopsy detected significantly more grade progressions than systematic biopsy in both the low and intermediate risk populations (P <0.001), but this difference was not significant at 4 years and 6 years. These results suggested that early use of MRI-targeted biopsy may exclude many of the aggressive tumors that should not be monitored under active surveillance protocols, Dr. Punnen suggested.

Genomic biomarkers can also be useful in electing prostate cancer patients for active surveillance, and 3 are currently available in the US: OncotypeDX Genomic Prostate Score (GPS) (Exact Sciences), Prolaris (Myriad Genetics), and Decipher (Veracyte). Oncotype DX GPS scores range from 0-100 and are based on a 17-gene signature built to represent the various oncogenic processes of prostate cancer proliferation. The Prolaris cell-cycle progression score serves as a surrogate for tumor proliferation. The test measures biologic aggressiveness of a given tumor through a panel of 31 cell cycle genes and 15 housekeeping genes. The Decipher prostate cancer classifier score (ranging from 0-1) is based on an expression profile of 22 coding and non-coding RNAs from the tumor sample. Decipher has been primarily utilized for prognostication after radical prostatectomy.

A study that characterized the genomic landscape of low-risk prostate cancer 6 demonstrated the genomic heterogeneity within prostate cancers that are traditionally considered “low risk” with almost 20% of patients having tumors at significant genomic risk as measured by the Decipher score.The potential role of these genomic tests in predicting disease progression remains uncertain, however.

An investigation of the utility of Oncotype DX GPS score in men from the Canary Prostate Active Surveillance Study (PASS) cohort found that GPS score did not predict patients who progressed or who were reclassified to a higher stage of disease.8 In a multi-institutional study of patients tracked through the prospective Michigan Urological Surgery Improvement Collaborative (MUSIC) and linked to the Decipher Genomics Resource Information Database (GRID), high-risk Decipher Biopsy score was strongly and independently associated with conversion from active surveillance to definitive treatment and treatment failure.9 Dr. Punnen explained that these results could be have been due to the higher scores prompting treatment versus inherent risk for progression.

More information about the utility of these tests in selecting patients for active surveillance is expected to come from the Genomics in Michigan to AdJust Outcomes in Prostate canceR (G-MAJOR) trial (NCT04396808), which is examining the clinical impact of gene expression classifier (GEC) testing in prostate cancer care.

The degree of tumor heterogeneity and how it impacts decision-making for active surveillance is currently being addressed at the University of Miami through the MRI Based Active Selection for Treatment Trial (MIAMI MAST; NCT02242773), Dr. Punnen explained. Patients enrolled in this trial, who have very low to intermediate risk disease, receive mpMRI of the prostate/pelvis and MRI- guided prostate biopsy at baseline and annually for 3 years subsequently. All positive tissue cores are sent for genomic profiling. Preliminary results showed that 21-62% of cases had more than one class of risk, with 2-19% showing >2 levels of risk, depending on the biopsy core sent for analysis and test used. Reassuringly, in 75-87% of cases, the core with the highest grade also had the highest genomic risk, Dr. Punnen noted. Comparing MRI guided prostate biopsy to standard template biopsy demonstrated that in 72-84% of cases, the MRI biopsy yielded the highest genomic risk cores.

Blood sent for baseline 4K score assessment revealed that the use of 4K alone yielded a high sensitivity (93%) but low specificity (19%) compared with MRI, which yielded lower sensitivity (79%) but higher specificity (58%). Thus, there was no difference in negative predictive value between 4K score and MRI, Dr. Punnen noted. Combining these modalities suggested that the using mpMRI and 4K score together could be used to reduce the number of false positive results, again with no difference in negative predictive values.

Based on this evidence, Dr. Punnen believes that MRI helps in the selection of men for active surveillance, although the role in monitoring remains unclear. Genomic markers may help in patient selection, but more data are needed from randomized clinical trials such as G-MAJOR. The role of molecular markers such as the 4K score also remains unclear, but Dr. Punnen is hopeful that there will be a role for molecular markers in monitoring.

Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.


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  6. Yerram NK, Long L, O’Connor LP, et al. Magnetic resonance imaging-targeted and systematic biopsy for detection of grade progression in patients on active surveillance for prostate cancer. J Urol. 2021;205(5): 1352-1360. DOI: 10.1097/JU.0000000000001547
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  8. Lin DW, Zheng Y, McKenney JK, et al. 17-Gene genomic prostate score test results in the Canary Prostate Active Surveillance Study (PASS) cohort. J Clin Oncol. 2020;38.(14):1549- 1557. DOI: 10.1200/JCO.19.02267
  9. Vince RA, Jiang R, Qi J, et al. Impact of Decipher Biopsy testing on clinical outcomes in localized prostate cancer in a prospective statewide collaborative. Prostate Cancer Prostatic Dis. Published online July 20, 2021. DOI: 10.1038/s41391-021-00428-ya

Presented at: AdMeTech 5th Global Summit on Precision Diagnosis and Treatment of Prostate Cancer (virtual), September 23-25, 2021


Exosome Dx, FoundationOne, Veracyte (Decipher Biosciences) Telix Pharmaceuticals.