An Introduction to a Novel Genomic Test and its Role in Improving Clinical Decisions: Part I: Prostate Biopsy Genomic Testing.
In 2013, the American actress Angelina Jolie made a life-altering decision that fascinated the public and made the cover of Time magazine . Based upon her family history and a genetic blood test for the BRCA1 gene, she was counseled that she had an 87% chance of developing breast cancer. This led to her decision to undergo a preventive double mastectomy. The Time article was titled “The Angelina Effect” and focused on the power of genomic medicine to guide clinical decision making. A family history can be considered part of “clinical information” and would certainly increase the odds of developing breast cancer, but only the genomic test increased those odds such that a preventive procedure became a reasonable strategy.
Where are we with genomic medicine in prostate cancer? The situation is distinct from the breast cancer scenario in that the inheritance pattern in prostate cancer relates to incidence of the disease, but not the biologic behavior of a tumor. Therefore we are looking to genomics to refine an individual’s risk of prostate cancer progression. In fact, prostate cancer has its unique qualities, in that the simple diagnosis of prostate cancer does not carry a significant risk of cancer mortality unless it is at the higher end of the Gleason scale . Cancers that are small in volume, clinically contained, and low in Gleason grade have very small progression rates and cancer-specific mortality and can often be observed . In contrast, there are lethal versions of prostate cancer that may require combination therapies to avoid progression and death . So let us explore this topic further by defining two common decision points for men with prostate cancer and demonstrate the role of genomic testing. In this part I article, we will explore the biopsy-related indications for genomic testing.
Diagnosis: Favorable Risk Prostate Cancer. Choice: Observe or Treat.
First, let us review the nomenclature used for “clinical information” so we can set that apart from genomic testing. There are two clinical settings where prostate cancer may be considered: 1) screening, meaning they have no complaints, but they meet common guidelines for testing with a digital rectal exam (DRE) and serum Prostate Specific Antigen (PSA), or 2) clinical evaluation, meaning they have a symptom or complaint that makes their doctor want to test them for prostate cancer. In either scenario, an abnormality of the DRE or PSA may lead to the recommendation to undergo a biopsy of the prostate. Of course, you could stop here and write an entire article about the pros and cons of PSA screening, but for this article we will just make the point that once a biopsy is performed that shows cancer, it really does “take over” the majority of the “clinical information” compared to the DRE and/or PSA that were the initial concerns (unless the DRE shows bulky disease or the PSA is > 10 ng/mL or rapidly doubling). A biopsy of the prostate (often abbreviated TRUS-BX for transrectal guided ultrasound biopsy) often includes 10-12 individual needle biopsies performed under ultrasound guidance. The size of each needle biopsy core may be up to 15mm. Therefore you have 3 very powerful pieces of information from a TRUS-BX: 1) Gleason Grade, 2) number of positive cores, and 3) % involvement of positive cores. Used together, we can now define a common clinical condition of the man who was either screened or evaluated for a symptom and as a result found to have “low grade-low volume” prostate cancer [5-6]:
Biopsy Grade: Gleason 3+3
Number of involved cores: 1 or 2
Percentage of involved cores: < 50%
PSA: < 4 or similar with enlarged gland
DRE: normal or very minimal findings
What happens when men undergo immediate treatment for this condition? They certainly can have favorable cancer control, but increasing evidence questions how much threat there was to begin with [4, 7]. Therefore, any long-lasting side effects they may experience from surgery or radiation would not be well balanced by a gain in cancer control. What happens when we recommend active surveillance? In general, we are correct in our decisions in approximately 70%, while the remaining 30% may be found to have higher volumes or grades of tumor on repeat TRUS-BX or a rapidly rising PSA that would trigger a delayed treatment. The majority of delayed treatments are based upon incremental changes in these features with favorable treatment outcomes, but there are occasional delayed findings showing significant upgrading or upstaging that cause concern [8-9].
So how can genomic testing such as Prolaris help? Prolaris is a test that looks at features of rapid cell turnover called Cell Cycle Progression (CCP) Genes . These are the genes that tell the cell to divide into two. The lack of regulation of cell division is a hallmark of all cancer. The test looks at the average expression of 31 CCP genes to generate a unique scaled result that can be yet another number to consider, but more usefully grouped into a descriptor such as “much more aggressive than average risk,” “equal to clinical risk,” or “much less aggressive than average risk.” Therefore if a man is unsure about whether or not to choose immediate treatment or active surveillance, the Prolaris test can give an estimate as to his 10-year cancer specific mortality if left untreated. The good news is that to have the test performed, the necessary materials are all in the biopsy tissue, and therefore no more invasive procedures are required. The bad news is that the test is expensive—around $3400—but not unreasonable compared to the cost of the biopsy itself or advanced imaging such as an MRI or PET scan. [PCRI note – Insurance coverage can vary with different insurance policies. See http://www.ProlarisTest.com or call (801) 584-1175 for more information.]
In my practice, I have found Prolaris helpful in some very young men who are considering active surveillance or just want maximum available information. I have found it even more useful in men who are interested in active surveillance but do not meet the above criteria for low-grade, low volume disease. See the following examples:
Example A: A 74 year old man with 3 positive cores of Gleason 3+4, normal DRE (T1c), and PSA 4.5 was evaluated and based upon his own research wanted a radical prostatectomy. However he had significant medical problems including heart disease, previous blood clots from surgery, and diabetes. Based upon the known clinical features of his cancer and overall health, we could make a reasonable prediction that he is unlikely to die of prostate cancer, unless the biology of his disease is much more aggressive than what we are seeing. His Prolaris score was in the “much less aggressive than average risk” category and a <2% chance of dying of prostate cancer in the next 10 years without definitive treatment. Therefore he changed his preference to active surveillance.
Example B: A 50 year old man was diagnosed with 3 small cores of Gleason 3+3 prostate cancer, normal DRE (T1c), and PSA 3.5. He would commonly be considered for a radical prostatectomy based upon this combination of multiple cores and young age. However he was extremely overweight to a degree that surgical complications and functional outcomes were a real concern. His Prolaris score was also in the “much less aggressive than average risk.” Therefore we have recommended an active surveillance plan with a major effort for him to lose weight in the event that future testing changes and he needs surgery.
Example C: A 55-year old healthy man has already been on active surveillance for 2 years with 1 core of Gleason 3+3, normal DRE (T1c), and PSA of 3.4. However at year 2, the repeat biopsy showed 1 small 1mm core of Gleason 4+3 and a second 1mm core of 3+3. For personal reasons and fear of side effects, he was just not ready to undergo definitive treatment, even though the Gleason 4+3 at his age is a significant concern. An MRI of the prostate was favorable—organ confined. His PSA levels and DRE have never changed. Six months later he requested another biopsy which showed 3 positive cores, but all Gleason 3+4 and less than 2mm. In aggregate, as his physician I would say that he has significant cancer that should be treated for cure with surgery or radiation. However, he still is adverse to side effects risk A Prolaris score was ordered on the most recent biopsy, which returned “less aggressive than average risk,” and he remains on active surveillance. He realizes that he may need therapy one day, but is satisfied with his risk/reward decision to wait until repeat testing shows a more concerning finding.
Genomic testing is now a reality in prostate cancer, and can be used to refine calculations of risk that can improve what we know from clinical features alone. The biopsy testing for Prolaris can specifically help define the risk of cancer-related mortality if left untreated—a calculation of particular interest to older patients with other risks of mortality. Future studies will certainly focus on how such genomic testing can help reduce the over-treatment problem associated with PSA screening and early detection. In part II of this article, we will examine the post-prostatectomy use of Prolaris, introduce some of the alternate genomic tests in the commercial marketplace, and critique our current position in genomic testing.
1. Kluger, Jeffrey (May 15, 2013). “The Angelina Effect: Time’s New Cover Image Revealed”. Time.com Retrieved May 19, 2013.
2. Albertsen PC, Hanley JA, Gleason DF et al. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998 280: 975-80.
3. Klotz L. Active surveillance for favorable-risk prostate cancer: background, patient selection, triggers for intervention, and outcomes. Curr Urol Rep 2012 13: 153-9.
4. Thompson I, Thrasher JB, Aus G, et al. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol 2007; 177: 2106-31.
5. Carter HB, Walsh PC, Landis P, et al: Expectant management of nonpalpable prostate cancer with curative intent: preliminary results. J Urol 167:1231-4, 2002
6. Ochiai A, Troncoso P, Chen ME, et al: The relationship between tumor volume and number of positive cores in men undergoing multisite extended biopsy: implication for expectant management. J Urol 174:2164-8, 2005 (discussion 2168)
7. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012; 367: 203-13.
8. Cooperberg MR, Carroll PR, Klotz L: Active surveillance for prostate cancer: progress and promise. J Clin Oncol 29:3669-3676, 2011
9. Davis JW, Kim J, Ward JF, et al: Radical prostatectomy findings in patients predicted to have low-volume/low-grade prostate cancer diagnosed by extended-core biopsies: an analysis of volume and zonal distribution of tumor foci. BJUI Int 105:(10):1386-91, 2010
10. Cuzick J, Berney DM, Fisher G, et al. Prognostic value of cell cycle progression signature for prostate cancer death on conservatively managed needle biopsy cohort. British Journal of Cancer 2012; 106: 1095-1099
More about Dr. Davis:
Dr. Davis serves as Assistant Professor in the Department of Urology at The University of Texas M.D. Anderson Cancer Center. He received his medical degree from The University of Virginia School of Medicine in Charlottesville, completed his residency in urology and surgery internship at the Eastern Virginia Medical School in Norfolk, and has also completed a fellowship in urologic oncology at M.D. Anderson. He is board certified in urology.