By: Dan Sperling, MD

All prostate cancers are not alike. The use of new genetic tests to identify which tumors are dangerous ushers in an age of truly individualized treatment planning for each patient. One such test is Prolaris® (Myriad Genetics, Salt Lake City UT), a type of test called a cell cycle progression test (CCP), which is based on an analysis of prostate biopsy tissue samples. Using the cells, it assesses the expression of certain genes during the cycle of cell. Because cancer cells do not duplicate in normal ways, scientists can measure abnormal levels of genes that “switch on” or “switch off” key points in the cell’s life cycle. In key studies, Prolaris® has been shown to be a statistically significant predictor of risk of disease progression and clinical outcomes, including mortality. [i] The test score gives a higher degree of confidence in matching treatment to disease. Cells with high levels of specific genes at cell cycle checkpoints result in a higher score, revealing a lethal capacity; such cases will dictate a more aggressive treatment. On the other hand, a low score suggests that tumor cells lack such warning signs, affording more time for doctor and patient to decide which treatment, if any, is required.

Two studies illustrate how Prolaris results led to a change in treatment plan. The first was published in June, 2014 (posted online in March, 2014).[ii] The study involved 305 patients who were prescribed the Prolaris CCP test. Their doctors filled out surveys on treatment recommendations before and after knowing Prolaris results and discussing them with patients. They also rated how much Prolaris influenced treatment decisions. The final decisions were confirmed by a third-party audit of patient charts once all survey responses were in. In all, 65% of cases changed the treatment decision based on test results. There was a 37.2% reduction in the number of cases where the initial recommendation had been interventional treatment. For the 141 cases in which a non-interventional treatment had been recommended, based on Prolaris 108 men stayed with the first recommendation whereas 33 shifted to interventional options, a 23.4% increase. Surgical interventions were reduced by 49.5% and radiation was reduced 29.6%. Thus, treatment reassignment correlated with Prolaris evaluations.

The second study was presented at the 2015 Genitourinary Cancers Symposium (Feb. 26-28, Orlando, FL).[iii] It was a prospective study of 816 newly-diagnosed PCa patients. Similar to the earlier study above, doctors completed questionnaires, prior to Prolaris results, on their treatment recommendations based on patients’ biopsy reports. Once the Prolaris scores were available, doctors then filled out surveys on revised treatment recommendation, doctor-patient treatment choice, and final treatment administered. Changes in treatment determined how much influence Prolaris had on decisions. It was found that 44% of initial recommendations changed, and 72% of those changes were reductions, across all modalities (prostatectomy, radiation, brachytherapy and hormonal therapy). Active surveillance increased.

Implications for focal treatment

Prolaris, and other genomic tests, clearly make a profound difference in matching treatment to disease. The ramifications for saving medical costs, not to mention patient quality of life, are huge. It must be a relief for a patient to be able to think, “I don’t need a whole-gland treatment at this time, and I have a lot of time in the future to monitor my disease.” While this would seem to point to greater utilization of active surveillance, that strategy comes with two main risks:

1. The potential to miss a treatment window, particularly a focal treatment if disease progresses in extent and/or in aggressiveness.
2. The psychological burden of living with a disease that gives no distinct warning of beginning to progress.

Therapies that are targeted to known tumor(s), such as focal laser ablation, are often met with skepticism by urologists who still believe that a radical treatment, such as prostatectomy, offers their patients the best chance for a cancer-free life, even for patients with low-risk disease defined according to PSA, Gleason grade and stage. Statistics show a downward migration in the age at which men are diagnosed, and younger men are particularly concerned about the sexual and urinary side effects of prostatectomy. Because PCa in younger patients may not be the same slow-growing cell line as that of a man at, say, age 75, focal ablation represents a middle ground between radical treatment and active surveillance. Prolaris offers information on the genetic nature of his prostate cancer; if test results show biomarkers that strongly suggest a high risk of disease progression, a patient can discuss with his doctor the pros and cons of a radical treatment vs. a focal (but aggressive) treatment.

In addition, biopsy-based Prolaris cannot reveal what a 3T mpMRI can: the location, size and shape of the tumor. The value of such imaging in the hands of an expert reader is two-fold: it is able to identify and monitor tumor activity, and it is used to guide and confirm focal ablation.

If a man is told his PSA blood test results are suspicious, we recommend the following steps:

1. A retest in three months, including free and total PSA, as well as the PCA3 urine test
2. If results are still suspicious, undergo a 3T mpMRI
3. If imaging reveals a suspicious lesion, have an mpMRI-guided targeted biopsy
4. If the pathology report is positive for PCa, consider submitting the tissue samples for Prolaris or similar analysis
5. Discuss the results and all appropriate treatment options, with your doctor.

It is a blessing to live at a time in which such advances facilitate best physician-patient relationships and clinical decisions.

[i] Bishoff et al. Prognostic Utility of the Cell Cycle Progression Score Generated from Biopsy in Men Treated with Prostatectomy; Crawford et al. Cell cycle progression score and treatment decisions in prostate cancer: results from an ongoing registry; Freedland et al. Prognostic utility of CCP score in men with prostate cancer after primary external beam radiation therapy; Cooperberg et al. Validation of a Cell-Cycle Progression Gene Panel to Improve Risk Stratification in a Contemporary Prostatectomy Cohort.

[ii] Crawford ED, Scholz MC, Kar AJ et al. Cell cycle progression score and treatment decisions in prostate cancer: results from an ongoing registry. Curr Med Res Opin. 2014 Jun;30(6):1025-31.

[iii] Shore, N et al. Impact of CCP testing on personalized treatment decisions: results from a prospective registry of newly diagnosed patients. #GU15, Genitourinary Cancers Symposium 2015 (Orlando, FL).