Promising Biomarkers Emerging Across the Spectrum of Prostate Cancer Care

E. David Crawford, MD

Researchers are making progress in identifying biomarkers and developing assays that will help clinicians improve the management of patients with prostate cancer from screening strategies to making therapy choices, according to E. David Crawford, MD.

“Biomarkers are a game changer in prostate cancer—something new and exciting and not that difficult,” said Crawford, a professor of Surgery, Urology and Radiation Oncology at the University of Colorado in Denver speaking at the 7th Annual Interdisciplinary Prostate Cancer Congress™, which Physicians’ Education Resources, LLC (PER®) hosted March 15 in New York City.

There is a need for better biomarkers to increase the rate of positive biopsies and to minimize the number of unnecessary biopsies by finding ways to distinguish between malignant and benign disease, said Crawford. Biomarkers also are needed for stratifying low-risk from high-risk tumors once a patient is diagnosed, more accurately staging and classifying disease, and monitoring and predicting clinical responses during therapy.

Crawford outlined the current biomarkers in use in the clinic including tissue, blood, and urine biomarkers as well as imaging modalities. He categorized promising indicators in development into three “biomarker buckets” based upon their potential utility: when to biopsy, when to rebiopsy, whom to treat or not treat (Table). Some of the markers have been introduced in commercially available tests while others remain in the process of clinical validation.

“There are a lot of biomarkers out there but there are only a few that are in use and it is not that difficult to understand which to use and when,” said Crawford.

Diagnostic Biomarkers

Prostate-specific antigen (PSA) screening can double the risk of a prostate cancer diagnosis for a man aged 50 to 70 years from 10% to about 20%, but this screening also decreases the risk of prostate cancer death by 20%, from 3% to 2.4%. “The urologist’s dilemma is that the PSA test is not perfect and not specific to prostate cancer,” said Crawford.

In a 2011 study, using a retrospective cohort, Crawford and colleagues identified a PSA of 1.5 ng/ mL as a safe cut-off for prostate cancer risk: prostate cancer rates for men with PSA levels of 1.5 ng/mL or higher were 15-fold greater compared with men whose PSA levels were lower than 1.5 ng/mL.¹ The study also showed that both Caucasian and African American men with baseline PSA values between 1.5 ng/mL and 4.0 ng/mL are at increased risk for future prostate cancer compared with those who have an initial PSA value below 1.5 ng/mL.

A higher PSA level is also a surrogate for an enlarged prostate, said Crawford. “Our way forward is to treat PSA as any other test ordered for patients, including lipid, cholesterol levels, and liver enzyme levels.” For the 70% who have normal PSA outcomes, a discussion about prostate cancer risk is not necessary and for the 30% who do have an elevated PSA level, the discussion with the patient should be done not by a general practitioner, but with a urologist or specialized internist.

The goal for diagnostic biomarkers is to improve sensitivity and specificity and to potentially identify an aggressive cancer early. About 1.3 million biopsies are performed in the United States each year yet only 241,000 (18.5%) of these result in a prostate cancer diagnosis, leaving 1 million men having undergone a negative biopsy. Moreover, about 25% of biopsies result in a false negative. “We biopsy patients because we worry about cancer and that worry does not completely go away even once the biopsy is negative,” said Crawford. Biopsies not only cause potentially unnecessary worry but are linked to morbidity. Up to 6.9% of men are hospitalized for complications that include bleeding, infection, sepsis, endocarditis, sexual dysfunction, and urinary symptoms.²

Although much research into genomic markers is under way, validating new markers is a long-term process, Crawford noted. “Almost every week there is a new signature that can identify a subgroup of prostate cancer patients,” he said. But, these are not relevant to clinical practice until validated, and currently, only a few diagnostic biomarkers are in use in the clinic.

One biomarker that may be useful for those patients with a PSA level between 4 ng/mL and 10 ng/mL, no additional risk factors, and no signs of cancer after a digital rectal exam, to decide whether a biopsy is necessary is the Prostate Health Index (PHI). This test is approved by the FDA for men 50 years or older who meet these criteria. Unlike the PSA test, which measures total PSA levels, the PHI combines measurements of free PSA that circulates in the bloodstream, pro- PSA (also called p2PSA). Pro-PSA, some studies suggest, is more closely correlated with prostate cancer compared with total or free PSA. The PHI score was better able to distinguish between a benign prostate condition and prostate cancer compared with the PSA score.³

Another biomarker test that can help clinicians make an initial biopsy decision is the PCA3 (prostate cancer gene 3) urinary test, which could help reduce the number of unnecessary repeat biopsies.

“This is an additional tool to help decide if a biopsy is necessary in men with PSA levels between 2.5 and 10 ng/mL,” said Crawford. Unlike PSA, PCA3 levels are high only in cancerous cells that are shed from the prostate and into the urine.⁴

Assays to Confirm Biopsy Results

After biopsies are conducted, several new assays can help guide clinicians in determining the next step.

If a first biopsy is negative, the ConfirmMDx test, which detects epigenetic changes around a lesion, utilizes residual tissue to help determine whether a repeat biopsy is needed. If the ConfirmMDx test is negative, patients would avoid a repeat biopsy and undergo routine screening by PSA and digital rectal exam. If the assay is positive, the clinician would manage the patient as though an atypical small acinar proliferation pathology result had been found and would consider performing a complete 12-core repeat biopsy.

For patients whose biopsies are positive, there are several new tests available. Oncotype DX Genomic Prostate Score (GPS) is a genomic assay that can provide a more accurate assessment of risk based on a patient’s individual tumor biology. For men with low- to intermediate-risk prostate cancer, the test has been prospectively validated as a tool to predict adverse pathology from a biopsy sample. The test assays the RNA levels of 17 genes that are associated with clinical outcome from a very small tumor biopsy, and can address tumor heterogeneity and be used to make a decision about whether a patient should undergo surgery or active surveillance.⁵ Another test to facilitate the decision of whether a patient should be treated for their prostate cancer is Prolaris, a prognostic genomic assay that assesses specific cell cycle progression gene mutations to identify both low-risk patients who may require minimal treatment and high-risk prostate cancer patients who should be treated more aggressively.⁶

A Test to Determine Therapy Postsurgery

In the treatment arena, it remains difficult to identify the subset of patients with more aggressive disease for whom adjuvant therapy is beneficial as there are not many obvious standard risk factors that can be used to assess aggressiveness of the cancer. Indeed, as many as half of the men who receive radiation therapy after a radical prostatectomy show no additional benefit from the adjuvant treatment.⁷

The Decipher test can help clinicians determine who should receive radiotherapy after surgery, said Crawford. Decipher is a genomic assay that assesses risk of progression following surgery and has been shown to be an independent prognostic factor of death from prostate cancer.⁸ A validation study found that those patients with a high Decipher score are most at risk for developing metastases to help make individual high-risk patient treatment decisions.

In conclusion, Crawford emphasized that adding genetic information to standard clinical variables provides independent prognostic information and represents important and incremental advances, but that markers must be validated using up-to-date biopsy tissue. “Emerging biomarkers hold great promise to improve prostate cancer risk assessment, reduce over-treatment, and facilitate more selective treatment for high-risk patients,” said Crawford.

Table. Evolving Prostate Cancer Biomarker and Assay Landscape

Biomarkers/Assays by Clinical Setting

Description

When to Biopsy

PSA

• PSA <1.5 ng/mL: Do nothing¹
• PSA >1.5 ng/mL: Repeat PSA, conduct adjunct testing¹

Prostate Health Index (phi)

Blood test for men with PSA 2-10 ng/mL²

Progensa PCA3 Assay

PCA3 gene detected in urine incorporated along with PSA into a score³

When to Rebiopsy

ConfirmMDx

• Detects field effect or halo of cancer at DNA level⁴
• Negative test rules out need for repeat biopsy
• Positive result rules in men who need further action

Progensa PCA3 Assay

See above

Prostate Core Mitomic Test (PCMT)

Analyzes existing biopsy tissue for molecular alterations⁵

TMPRSS2-ERG

Fusion gene levels associated with cell migration and invasion⁶

PTEN

Gene deletion levels associated with disease progression⁷

Whom to Treat or Not Treat

Oncotype DX

17-gene assay stratifies for risk, predicts aggressiveness⁸

Prolaris

46-gene test predictive of biochemical recurrence or metastatic disease⁹

Decipher

22-marker genomic classifier score predictive of metastasis¹⁰

CTCs

• Baseline CTCs prognostic for docetaxel-based cohort
• Rising CTCs correlate with poorer OS¹¹

TMPRSS2-ERG

See above

PTEN

See above

CTCs indicates circulating tumor cells; OS, overall survival; PSA, prostate-specific antigen.

1. Crawford ED et al. BJU Int. 2011:108(11):1743-1749. 2. Catalona WJ et al. J Urol. 2011;185(5):1650-1655. 3. De la Taille A et al. J Urol. 2011:185(6):2119- 2125. 4. MDxHealth website. http://goo.gl/jjAIv3. 5. Mitomics website. http://goo.gl/IqOs3J. 6. Tian TV et al. Oncogene. 2014;33(17):2204-2214. 7. Yue S et al. Cell Metab. 2014;19(3):393-406. 8. Cooperberg M et al. 2013 AUA Annual Meeting. Abstract 2131. 9. Cuzick J et al. Lancet Oncol. 2011;12(3):245-255. 10. Karnes et al. J Urol. 2013;190(6):2047-2053. 11. Goldkorn A et al. J Clin Oncol. 2014;32(11):1136-1142.

References

1. Crawford ED, Moul JW, Rove KO, et al. Prostate-specific antigen 5-4.0 ng/mL: a diagnostic challenge and danger zone [published online June 28, 2011]. BJU Int. 2011;108(11):1743-1749.
2. Loeb S, Carter HB, Berndt SI, Ricker W, Schaeffer EM. Complications after prostate biopsy: data from SEER-Medicare [published online September 23, 2011]. J Urol. 2011;186(5):1830-1834.
3. Catalona WJ, Partin Aw, Sandra MG, et al. A multicenter study of [−2]pro-prostate-specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range [published online March 17, 2011]. J Urol. 2011;185(5):1650-1655.
4. De la Taille A, Irani J, Graefen M, et al. Clinical evaluation of the PCA3 assay in guiding initial biopsy decisions [published online April 15, 2011]. J Urol. 2011;185(6):2119-2125.
5. Cooperberg M, Simko J, Falzarano S, et al. Development and validation of the biopsy-based genomic prostate score (GPS) as a predictor of high-grade or extracapsular prostate cancer to improve patient selection for active surveillance. American Urological Association Annual Meeting; San Diego, CA; May 8, 2013. Abstract 2131.
6. Cuzick J, Swanson GP, Fisher G, et al. Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study. Lancet Oncol. 2011;12(3):245-255.
7. Ghadjar P, Zwahlen D, Aebersold DM, Zimmerman F. Postoperative radiotherapy after radical prostatectomy: indications and open questions [published online February 28, 2012]. Prostate Cancer. 2012;2012:963417.
8. Karnes RJ, Bergstralh EJ, Davicioni E, et al. Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population [published online June 11, 2013]. J Urol. 2013;190(6):2047-2053.