Edward Weber, MD

ACTIVE SURVEILLANCE: Patient Selection, Outcome and Monitoring for Gleason Grade Progression.
Question: Why not be treated at initial diagnosis of prostate cancer— and hope for cure?
Answer: Because all treatments are associated with unwelcome adverse effects that most men would prefer to avoid. Who should receive immediate treatment, and which men may safely delay treatment, preserving quality of life, — and with careful monitoring and timely intervention experience a similar outcome as if treated initially. That is the subject of this Commentary: patient selection for active surveillance (AS) and new techniques for monitoring for progression during AS.

Currently, eligibility for AS is based on clinical/pathological and biomarker features that define low- or favorable intermediate-risk prostate cancer: Gleason score 3+3 (Grade Group1) and Gleason score 3+4 (Grade Group 2); < 20% Gleason pattern 4; less than 50% positive biopsy cores and having only one NCCN intermediate risk factor (i.e., PSA 10-20 ng/ml, Gleason score 7 and cancer limited to the prostate). A PSA Density of <.15 and an MRI PIRAD score of 1 or 2 support AS. Although Gleason Grade Group 1 is to a small extent heterogeneous, the behavioral heterogeneity of Gleason score 7 grouping has led to a sub-classification into “favorable (Gleason 3+4; Gleason Grade Group 2) and unfavorable intermediate-risk cancer (4+3; Gleason Grade Group 3), the latter not advised for AS. The concern regarding the extent of Gleason pattern 4 in Gleason score 3+4 is based on the understanding that prostate cancer cells with pattern 4 characteristics have the potential to invade and metastasize. Patients with <5% pattern 4, are deemed satisfactory for AS, whereas a rise toward 20% increases the advisability for early intervention. The NCCN guidelines “prefer” AS as opposed to initial treatment for low-risk patients and allows consideration of AS for men with favorable intermediate-risk cancer with low PSA density (< .15) and low tumor volume ( i.e., < 2 positive cores), low genomic risk score and low percentage of Gleason pattern 4, i.e., <5%. Brief Summary of Outcome of Trials of Active Surveillance in Patients with Gleason Grade Groups 1 and 2: An extensive current review (Mukherjee et al., Journal Clinical Medicine, Dec. 2023) of outcomes for men with localized cancer (low-risk and favorable intermediate-risk) was based on a review of 712 studies from which 25 provided sufficient detail. Two representative studies will be briefly summarized: Courtney et al., (J.NCCN. 2022): Men on AS [8726 low-risk (LRPC) and 773 favorable intermediate-risk (FIRPC)] patients were followed for a median of 7.6 years. Metastasis-free survival at 10 years was 98.5% vs 90.4%; cancer-specific survival was 99% vs 96%, respectively. Mukhergee et al., (Eur. Urol. Open Sci., 2023): For men on AS (276 LRPC and 96 FIRPC) with median follow-up of 4.5 years. “… there was no significant difference in the median duration of AS between the two groups (32.5 months for IRPCvs 36 months for LRPC, p=0.53.” During the course of AS 30% had disease progression and were offered active treatment. The overall survival probability at 5 years for LRPC and FIRPC was 93% for both, and at 10-years 90% vs 83%s respectively. Studies from John Hopkins and Toronto report 98-99% cancer-specific survival in carefully selected and monitored men with low- and favorable intermediate-risk cancer despite 36% to 50% conversion to treatment during AS due to Gleason grade progression (Data from NCCN 2022 guidelines). The excellent survival figures in all these studies point to the effectiveness of treatment in those men who progressed during AS. The equivalence of outcome at intervention for carefully selected and monitored men on AS compared to those men treated with surgery at diagnosis has been multiply reported. Epstein, Carter et al., (Journal Urology, 2017) reported, ”Patients on active surveillance reclassified to grade group 2 or greater are at no greater risk for treatment failure than men newly diagnosed with similar grades.” Genomic Classifiers (Decipher, Prolaris, OncotypeDx) provide greater prognostic accuracy than standard clinical/pathological classifications (cited above) for estimating progression in men with localized prostate cancer considering AS. At the 2023 meeting the Society of Urologic Oncology Sheng et al. (Abst 237) reported that in a study of 235 men, Decipher Genomic Classifier (range of increasing concern for metastases and mortality extend from 0 -1.0) was associated with an upgrade to adverse pathology in men with a scores above 0.4 (p=.002) and above 0.6 (p=.006) - both values not suitable for men considering AS. A second study by Khandaker based on data from the Miami Active Surveillance Trial reported similar findings: Decipher scores >0.4 and increasingly above 0.6 were associated with adverse Gleason grade progression which would signal early intervention as opposed to AS.

The Next Step Forward: Predicting Future Progression Dynamically During AS as Opposed to Predictions Made Only at Baseline.

The clinical/pathological classification systems cited above offer prognostic (as opposed the predictive) information to guide patient selection but are not patient-specific. For example, a Decipher score of, say, 4.3 establishes a concerning level of risk but leaves the patient and physician a significant management decision about how to incorporate that extent of risk in a management plan. Studies using statistical analysis (see Cooperberg below) and artificial Intelligence (see Lee and Nayan below) provide dynamic patient-specific predictions of adverse grade progression during the course of AS.

Cooperberg et al.,(JAMA Oncol, Aug 2020) addressed this issue in “Tailoring Intensity of Active Surveillance for Low-risk Cancer Based on Individualizing Prediction of Risk Stability.”
The Canary Prostate Active Surveillance Study (PASS) involves 9 academic medical centers and based their study on 850 very explicitly followed patients for at least 5 years following enrollment. Their product provided an individualized prediction at the time of diagnosis or during AS of ‘non-reclassification’ at 4 years – i.e., information that might guide continued participation in AS or a switch to intervention. “The Canary model was built to be calculable at any given landmark time or event in the course of active surveillance.” Their findings suggest that “based on an individual’s risk parameters, that many men may be safely monitored with a substantially less intensive surveillance regimen.”

Two other studies employed AI to predict grade progression during AS [Lee et al. (Nature Prostate Journal, Digital Medicine, Aug 2022) and Nayan et al. (Urol Oncol. Apr 2022)]. Both provided a guideline regarding future progression. Using AI and incorporating interval monitoring data (PSA, MRI and biopsies) each study estimated an ongoing “real life” prediction at any time during AS of the risk of future Gleason grade reclassification, information that could influence the decision to withdraw from AS and switch to active intervention.

BOTTOM LINE:

Active Surveillance is the preferred management option for men with low- and favorable intermediate-risk prostate cancer and has been shown to yield excellent outcomes. Genomic classifiers are further refining patient selection. Statistical analysis and artificial intelligence provide dynamic risk assessment for grade progression during the ongoing course of AS.

Background

Oligometastatic prostate cancer (omPC) designates the status of having 3 to 5 metastatic lesions at diagnosis with an untreated primary or a similar extent of spread at recurrence after primary therapy. Metastasis directed therapy (MDT) focuses radiation to those several lesions. This situation is increasingly prevalent due to the more frequent use of PSMA PET imaging and in 2018 the incidence of hormone sensitive metastatic PC prostate cancer (mHSPC) at diagnosis was 8.2% (Vandenberg et al. Prostate Cancer and Prostatic Diseases, 2023), occurring mainly in men with high-risk cancer. Metastatic hormone sensitive PC can be found in men studied by PET imaging whose PSA is rising following primary therapy, converting non-metastatic HSPC to metastatic hormone resistant PC (mHRPC).

In their study of 200 men with rising PSA values after primary therapy before hormone intervention, PSMA PET scans identified metastases beyond the prostate in 55% of men, pelvic nodal disease in 20% and local recurrence in 24% (ibid). Studies comparing the genomics of denovo mHSPC with recurrent mHRPC have found — likely due to the delay in diagnosis allowing time for mutations to develop — that the cancer in the recurrent state is more aggressive.

Focal radiation therapy (e.g. with CyberKnife radiation) achieves >95% local control of oligometastatic lesions, but the major deficiency of MDT is the subsequent emergence of un-imaged polymetastatic disease. Metastatic prostate cancer is biologically heterogeneous with some metastatic sites remaining indolent and others rapidly progressing to polymetastatic spread. The current research challenge is to identify biologic markers and molecular signatures to predict metastatic behavior and guide therapy based on which men would benefit from MDT.

Three treatment options for oligometastatic prostate cancer were reviewed in PCa Commentary Vol. #182. In brief, MDT without ADT, MDT with ADT, and MDT combined with intermittent Xtandi. All had improved overall survival as compared to ADT only. However, in those studies patients were selected based on CT and technetium bone scans, not the more sensitive PSMA PET imaging, which detects metastases earlier at diagnosis and at recurrence. Current patient selection is based arbitrarily on the number and location of treatable metastatic lesions.

Conventional Predictors of Progression Following MDT for Oligometastatic Prostate Cancer

Analysis of early trials comparing MDT with no ADT (Deek, JCO 2022) found that men with mutations in the DNA damage repairs genes, i.e. BRCA 1, 2 and ATM, were at high risk for early failure. Radiographic progression-free survival for those without deleterious mutations compared to those with mutations was 22.6 months vs 10 months, respectively.

Another analysis found that the size, location of metastatic lesions and PSA doubling time in men with oligorecurrent disease affected outcome (Franzese, Clin & Experimental Metastases, 2022). In their study with PSMA PET imaging the median size of metastatic lesions was 4 cm.

Local control at 1 and 2 years was 94% and 92%; progression-free survival at 1 and 2 years, 80% and 69%, with a median time to progression of 33.7 months. The best outcomes were associated with pelvic nodal disease, followed by extra-pelvic nodal spread or metastases to bone. The take-away from these data is the need for more accurate predictors based on molecular features to guide selection of men who will benefit most from MDT.

Liquid Biopsy

The current quest is to identify a molecular signature to predict the aggressiveness of oligometastatic lesions to determine the likelihood of rapid progression to polymetastatic disease.

Tumor cells circulate (CTC) in the blood pre-diagnosis and increasingly as the disease progresses. Cell Search, an FDA approved test, has established that 5 or more CTC in 7.5 cc of blood augers a poor prognosis and less than 4 is associated with a better prognosis. Sophisticated genomic sequencing – usually referred to as ‘next generation sequencing,’ can analyze the DNA and identify the associated mutations of these circulating cells. The analysis of DNA debris from these cells – referred to as circulating tumor DNA (ctDNA) summarizes the contribution of ctDNA of the entire malignant population, an advantage since the genomes of various metastatic lesions may differ, rendering a biopsy of one site a limited representation of the overall metastatic burden.

Most circulating free DNA is shed from normal cells; in cancer patients only 0.01 – 5% of the circulating free DNA is derived from tumor cells. After the primary prostate tumor has been removed or treated, ctDNA characterizes the totality of micro- or macro metastases – and it is this ctDNA that is being evaluated for clues as to the aggressiveness of the oligometastatic lesions to guide the appropriateness of MDT.

A Major Effort

“Stratification of Oligometastatic Prostate Cancer by Liquid Biopsy: Clinical Insights from a Pilot Study,” Colosini, Triggiano et al, Biomedicines, 2022. In their earlier abstract (GU Cancers Symposium, 2018) they described the background of their study: “oligometastatic prostate cancer (OPC) may represent the initial stage of an unfavorable, rapid progression to a polymetastatic state, or the expression of a real oligometastatic phenotype related to a condition of stable disease for a long time.” They studied 28 men with hormone naive OPC, imaged with 11C-Choline PET CT, sequencing a panel of 37 prostate cancer relevant genes in circulating free DNA and microRNA. The genomic analysis was repeated frequently to evaluate the evolution to disease progression. The commonest adverse mutations were ATM, 50%, BRCA2, 39% and BRCA1 21%.

Having established the pre-MDT genomic characteristics of the men, their goal is in the subset follow-up to relate the molecular biomarker to outcome. The study is immature for analysis, but it is hoped that the outcome will provide guidance for patient selection to MDT.

BOTTOM LINE

Metastasis directed therapy prolongs survival in men with oligometastatic prostate cancer. It is hoped that genomic analysis with liquid biopsy will provide guidance for improved patient selection.