Favorable-Risk Prostate Cancer in the Age of Precision Medicine

Active Surveillance and Drug Treatment Opportunities

William J. Catalona
Northwestern University Feinberg School of Medicine, Chicago
Matthew R. Cooperberg
University of California-San Francisco
Peter R. Carroll
University of California-San Francisco
John S. Witte
University of California-San Francisco
Scarlett L. Gomez
University of California-San Francisco
Denise M. Scholtens
Northwestern University Feinberg School of Medicine, Chicago
Franklin D. Gaylis
Genesis Healthcare Partners San Diego
Ronald C. Chen
University of North Carolina, Chapel Hill
Stacy Loeb
New York University School of Medicine and Manhattan VA

he heterogeneous nature of prostate cancer (PCa) poses treatment challenges. It is not currently possible to accurately identify patients harboring aggressive disease who may be compromised by delaying treatment. Thus, there is a need to develop more accurate evidence-based knowledge for distinguishing between aggressive and indolent PCa. The major challenge is the lack of accurate clinical, biochemical, pathological, and genomic indicators.


In the US, PCa is the most common visceral cancer in men, accounting for 20 percent of all new cancers, and the second leading cause of cancer death. The introduction of prostate-specific antigen (PSA)-based screening dramatically increased the detection of early aggressive PCa, leading to a more than 50 percent decrease in US PCa mortality rate. However, PSA screening also has increased the detection of non-life-threatening cancers that often do not require curative treatment and carry risks for urinary, bowel, and sexual complications. Also, delaying treatment in men with unrecognized aggressive disease may compromise curative outcomes.

Risk Stratification for Disease Progression

The grading system for PCa, devised in the 1960s and called the Gleason “score,” is a time-honored indicator of the biological aggressiveness of the tumor based on the degree of normal gland formation in the tumor and remains central to risk stratification. The Gleason score as well as PSA level, clinical stage, and the number of positive biopsy cores provide the risk strata that newly diagnosed prostate cancers are assigned.

Active Surveillance and Challenges in Its Implementation

Active surveillance (AS) is a management strategy in which men are conservatively followed closely with regular clinical assessments. It was introduced to reduce overtreatment of low-risk PCa. AS protocols differ but usually involve PSA testing every six months and digital rectal examination of the prostate every 12 months, with follow-up surveillance prostate biopsies every 1-2 years or less frequently if biopsy results remain unchanged. The intent is to ensure the accuracy of categorizing the tumor as favorable risk, and the goal is to avoid surgery or radiation, if possible. If there is evidence of more aggressive PCa (i.e., increase in tumor volume, tumor grade, or PSA levels), curative treatment, including targeted drugs, can be provided within the window of curability. MRI scans and genomic profiling can be used to help define and monitor disease status, but they are not yet an adequate substitute for surveillance biopsies.

PCa treatment decisions are based on the diagnostic biopsy, but biopsy sampling errors can underestimate or overestimate the aggressive potential of the tumor (i.e., by obtaining multiple biopsy samples from the same small region of the prostate, especially when guided by imaging). Existing biomarkers and imaging improve, but do not guarantee, the ability to detect aggressive PCa. These difficulties with the accuracy of risk classification are a barrier to the implementation of AS. Research efforts are underway to more reliably define a patient’s risk category so that the disease management can be “customized” to individuals.

Active Surveillance Controversies

Controversial aspects of AS include whether younger men, men of African ancestry (AA), and men with Gleason score 3+4 (GG 2) cancers are appropriate candidates. Other controversies include the use of AS or drug therapies for carriers of germline mutations.

Age: In general, older PCa patients have more aggressive tumors, an increased risk for biopsy grade reclassification, and higher PCa death rates. Therefore, for very healthy older men, AS may result in greater net harm than benefit. In contrast, younger patients are generally diagnosed earlier in the evolution of their cancer and are less likely to exhibit early reclassification to a higher grade tumor. However, because of their longer period of risk, younger men may have more long-term grade reclassification. Individual patient preferences and characteristics are important to consider in determining the optimal approach.

Race/Ethnicity: AA men have higher incidence and mortality rates from PCa than men of any other racial or ethnic group and may have a higher risk for reclassification. AA men with low-risk disease also have higher genomic risk scores, suggesting that disparities in favorable-risk disease may be driven by biological differences in tumors.

Intermediate-Risk PCa: Among patients whose tumors contain Gleason pattern 4, AS should be reconsidered if there is a high PSA density (i.e., a PSA-to-prostate volume ratio higher than 0.15), high-risk features on MRI scanning, adverse genetics/genomics, cribriform histology, or larger tumor volume.

Genetics: Familial carriers of certain pathogenic germline mutations of genes associated with DNA repair, such as BRCA1, BRCA2, and ATM, have more aggressive tumors and a higher risk for reclassification on AS. Although favorable-risk PCa is often considered uniformly harmless, it can occur in a diverse genomic landscape that includes aggressive tumor features.

AS and Precision Medicine: Drug Treatment and New Biomarker Opportunities

The prior discussion of controversies suggests the opportunity for using drugs to reduce the risk of progression in selected patients on AS. For instance, 5-alpha-reductase inhibitors (5-ARIs) have been used to complement AS; however, they require clinicians to make appropriate adjustments to avoid masking signs of disease progression (e.g., increasing PSA levels in patients taking 5-ARIs are concerning for disease progression). Over the past two decades, comprehensive analyses have uncovered targetable genomic alterations in primary as well as metastatic PCa, and preclinical models of PCa biology, including 3D cell culture (such as spheroids, prostaspheres, and organoids), have expanded our understanding of prostate cancer progression. This research could lead to drug treatments for delaying progression of early stage PCa and better methods for monitoring patients during AS. For example, BRCA or other germline DNA repair mutations occur in some PCa patients and are known to put these patients at higher risk for cancer progression. Although they have not been evaluated in low-risk PCa, PARP (poly ADP ribose polymerase) inhibitors could prove to be beneficial in these patients. Recent research on the genomic landscape in PCa has identified other targetable pathways, and immunotherapy may also prove to be helpful. Perhaps most important is the promise of better monitoring of disease by evaluating biopsies against panels of genomic alterations, applying sophisticated techniques such as single cell analysis for evaluating biopsies, and, with these new techniques, being able to monitor patients more frequently and less invasively by liquid biopsy.

Results of AS

The rates of patients remaining on AS vary among studies, depending on age, race/ethnicity, and the stringency of the eligibility criteria. One third of patients switch to another management within three years; half switch within five years; and 60 percent switch within ten years. Overall, 30-40 percent of AS patients subsequently are found to have more aggressive disease than initially suspected.

Summary and Conclusions

AS is an important management strategy to mitigate the overtreatment of men whose PCa is not life-threatening; however, it remains challenging to accurately identify patients harboring occult aggressive disease who may be compromised by delaying treatment. Current AS guidelines issued by professional organizations are based largely on expert opinion, and there is an unmet need to improve the appropriate uptake and implementation of AS. There also is a need to develop better methods for distinguishing between aggressive and indolent disease and for whom AS should be performed at increased or reduced intensity. There is some evidence that high-risk men, such as those with a positive family history, DNA repair deficiencies, and AA men have a higher risk for prostate cancer mortality. These men need more intensive surveillance and may need multi-modality treatment including molecular targeted drug therapy. This cohort of men at high risk of progression are good candidates for evaluation of new drugs per the tenets of personalized medicine. The current uptake of AS for low- and favorable-risk PCa as well as the performance of AS also need to be improved. Genetic and genomic testing and new imaging methods, including MRI and PET scans, may prove more useful in this regard. The cost-effective integration of biomarkers and imaging methods will likely improve the appropriate selection of patients for AS and treatment. Evidence-based information has great potential for improving the quality of care provided to patients with favorable-risk PCa.

References available upon request. Please direct all inquiries to William J. Catalona at wcatalona@nm.org.