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Improving methods to identify indolent versus aggressive prostate cancer

At the 2014 AACR – PCF Advances in Prostate Cancer Research Conference, Dr. Matthew Cooperberg demonstrated that adding biomarker tests to current clinical predictors significantly improves the identification of which prostate cancer patients should undergo active surveillance vs. immediate treatment.

January 28, 2014 — “If we don’t fix the problem of prostate cancer overtreatment, we will lose screening.” Those haunting words, spoken by PCF-funded Young Investigator Dr. Matthew Cooperberg last week at the 2014 AACR – PCF Advances in Prostate Cancer Research Conference, in San Diego, had physician and scientist attendees abuzz. They knew that Cooperberg, a urologic oncologist at the University of California, San Francisco (UCSF), was quite likely right—overtreatment of prostate cancer was an important driver of the 2012 decision by the United States Preventative Services Task Force to recommend against routine screening for prostate cancer in men of any age.

Attendees fully understood what’s at stake: losing screening in the general population will mean upticks in prostate cancer deaths—reversing a nearly 45% decline in mortality rates since screening started—even as overtreatment subsides. Overtreatment of prostate cancer patients is a problem in the U.S. Approximately 30-40% of men who have undergone surgical or other therapeutic interventions to treat their prostate cancers likely had indolent, slow-growing tumors that would never have become a threat to the man’s lifespan or health. Active surveillance—a program of monitoring low-risk prostate tumors over time for signs of progression, rather than performing immediate treatment—is substantially under-utilized in men with low-risk disease. And frustratingly, on the other hand, many patients with high-risk tumors are never offered a chance at curative therapy. The crux of the problem lies in the uncertainty of the accuracy of current predictors of tumor aggressiveness, and the unknown comparative benefits of various treatment approaches, leading physicians and patients to opt for a better-safe-than-sorry approach, which too often leads to overtreatment. Such overtreatment is costly both economically and physically, as treating prostate cancer can cause unpleasant and long-lasting side effects in some men.

Dr. Cooperberg studies various biomarkers as a means to improve or refine the stratification of indolent from aggressive tumors in newly-diagnosed prostate cancer patients. He and colleagues at UCSF developed the CAPRA score as a means to predict whether a patient has low, intermediate, or high risk prostate cancer; the scores generated are used to guide treatment decisions. CAPRA scores integrate PSA levels, Gleason score, clinical T stage, patient age, and the percentage of prostate biopsy tissue containing malignant cells. This methodology is 80% accurate in predicting the likelihood of progression to fatal disease. However, the remaining 20% uncertainty rate is one important factor which is likely to continue to drive overtreatment, so further improvements to risk stratification are needed.

In his talk at the AACR – PCF Conference, Cooperberg presented results from studies in which several biomarker tests were evaluated for their ability to refine CAPRA and related scores in predicting tumor aggressiveness. Many candidate assays are in different stages of pre-clinical and clinical development. These assays, or tests, assess aggression-associated biomarkers including mutations or alterations in tumor DNA, expression levels of tumor-associated genes, and altered metabolic analytes in prostate cancer tissues, blood, urine, or prostatic secretions, or detected by imaging technologies such as MRI and PET.

Combining clinical information with genetic information yields better outcome predictions

The Myriad Prolaris Assay examines the expression of 31 genes that regulate tumor cell growth in prostate biopsy specimens to predict the risk of lethal disease. The Oncotype DX Genomic Prostate Score (GPS) is a similar test that examines the expression of 17 aggressive tumor-predictive genes in biopsy specimens. Both of these tests on their own, fare well in predicting patient outcomes. Both, furthermore, contribute significant, independent prognostic information above and beyond what can be measured clinically using the CAPRA score or related tools. Combining clinical information from the CAPRA score with the information expressed in either of these genetic scores yielded improved predictions, better than what could be achieved with clinical or genetic information alone. Dr. Cooperberg concluded that “emerging biomarkers contribute independent predictive information, and offer great promise to improve prostate cancer risk assessment and reduce overtreatment.”

How this information will ultimately be used by physicians, and communicated to patients in order to understand treatment decisions, will bring additional challenges. Dr. Cooperberg , together with PCF-funded researchers Dr. Peter Carroll and Dr. June Chan at UCSF, led a team that has recently received a highly competitive DOD Transformative Impact Award, which will further develop and validate the use of these biomarker tests, integrate this information with clinical and lifestyle risk factors to improve patient prognosis, and create tools to help physicians explain this information to patients.

PSA screening has led to a significantly larger number of men finding cancers and receiving treatment earlier in the course of disease, thus reducing prostate cancer mortality rates. Efforts to better define which of these men need immediate treatment will reduce both overtreatment and undertreatment of patients, but such change is a multidisciplinary effort that requires awareness and action on the part of the entire medical and research community. That Cooperberg’s closing statement garnered the attention of AACR-PCF conference attendees indicates that clinicians and scientists are now wide awake to this challenge.

The 2014 AACR – PCF Advances in Prostate Cancer Research Conference was held from January 18-21, 2014, in San Diego, CA.

Andrea Miyahira
Dr. Andrea Miyahira has a PhD in cancer immunology, and is Director of Research at the Prostate Cancer Foundation.