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GPS
GPS commonly refers to Global Positioning System, the satellite-based system that provides geo-positional guidance that helps with directions and navigation. Another GPS–the topic of today’s entry–is Genomic Prostate Score. Both GPSs provide invaluable guidance, putting one’s position in clearer perspective and aiding in the process of navigation. In the case of the Genomic Prostate Score, “putting one’s position in clearer perspective” means determining the risk of aggressiveness of a prostate cancer and “aiding the navigation process” refers to the assistance provided in informing the treatment decision process as to whether active surveillance or active treatment is the most prudent option.
GENOMICS VERSUS GENETICS
Genomics is an interdisciplinary field of biology focusing on the structure, function, evolution, mapping, and editing of genomes, an organism’s complete set of genes. Genomic tests examine gene expression within a sample of tissue from the biopsy, providing information regarding cancer biology and aggressiveness. This is in distinction to genetic tests that screen for inherited risk factors, information that can be helpful to assess risk of acquiring a cancer and response to certain treatments. Whereas genetic testing seeks risk factors present in every cell in the body, genomic testing seeks to uncover the abnormal genes present only in the cancer tissue. Genomic testing, the genetic sequencing of prostate cancer biopsy tissue, has the ability to identify the molecular “signatures” that underlie the cancer.
Prostate cancer can be confusing not only because every individual case is unique, but also because cancer cells are often present in multiple locations within the prostate (multifocality) and have variable characteristics (heterogeneity). Despite these confounding factors of multifocality and heterogeneity, there is consistency in the genomics of any given prostate cancer and that is the reason why studying the genomics within a sample of biopsy tissue can provide clarification. The genomic study can assess the expression or lack thereof of specific genes that promote biological pathways towards prostate cancer aggressiveness.
GENOMIC PROSTATE SCORE/ONCOTYPE DX TEST
The challenge for those of us who treat prostate cancer is to distinguish indolent, slow-growing cases that are unlikely to spread or threaten one’s life and do not require treatment from more aggressive cases that do require treatment. The Oncotype GPS is one of the valuable tools that helps urologists make this distinction.
Genomic Prostate Score (GPS) a.k.a. Oncotype DX, is a biomarker test developed by Exact Sciences that is often utilized in the process of prostate cancer risk assessment. This test is performed at the time of initial diagnosis to determine the aggressive potential of any given prostate cancer. It has been found to be a powerful predictor of aggression that provides information that informs the best course of management.
Molecular alterations, e.g., translocations, deletions, fusions, overexpression, rearrangements, activation, chromosomal losses, etc., contribute to and drive the development of any cancer, including prostate cancer. Prostate cancer is initiated and progresses based upon these cellular pathways being co-opted. Of primary importance in the promotion of most prostate cancers is deregulated and corrupted androgen receptor signaling.
The GPS test uses prostate cancer tissue from the biopsy to evaluate the expression of 17 genes associated with aggressive prostate cancer. The more of these genes that are expressed (the more gene activity), the more potentially aggressive any given prostate cancer is. Four aggressiveness pathways are measured by using a quantitative polymerase chain reaction method. Using multiple biological pathways has found to be more predictive than any single pathway alone. The genetic aggressiveness pathways include the following (the specific genes are noted in capital letters often followed by a number):
Androgen signaling: AZGP1, FAM13C, KLK2, SRD5A2
Cellular organization: FLNC, GSN, GSTM2, TPM2
Stromal response: BGN, COL1A1, SFRP4
Cellular proliferation: TPX2
Reference genes (housekeeping controls): ARF1, ATP5E, CLTC, GPS1, PGK1
This is scientifically complex, but if you are interested in more of the specifics and details of these pathways and genes, see Table I at the end of this entry.
The GPS is a weighted average of gene expression levels that is reported on a score scale of 0 -100. The higher the score, the greater the risk for biologically aggressive prostate cancer. To reiterate, the GPS test is beneficial for men with newly diagnosed prostate cancer to aid in making an informed decision regarding management, specifically to help guide who is a candidate for active surveillance versus who is a candidate for surgical or radiation therapy. The GPS test is particularly helpful for men with Gleason score 6 very low risk and low risk categories as well as Gleason score 7 (3+4) intermediate risk category prostate cancer.
The combination of Gleason score and genomic prostate score is the best predictor of aggressive prostate cancer. A genomic prostate score of < 20 is rarely associated with the potential for metastatic disease or death. Measuring the gene activity across the aforementioned four important genetic pathways, in conjunction with clinical risk factors is capable of providing risk stratification and predicting the risk of adverse pathology (Gleason 4+3 or higher and or tumor extending beyond the prostate capsule or to seminal vesicles) if prostatectomy were to be done, as well as predicting progression, metastasis, and prostate cancer death.
Table I
ANDROGEN SIGNALING GENES
AZGP1: A low “Zinc-alpha 2 glycoprotein” expression is associated with a shorter time to castrate-resistant prostate cancer.
FAM13C: “Family with Sequence Similarity 13 Member C” overexpression is a strong predictor of poor clinical outcome in prostate cancer.
KLK2: “Human kallikrein 2” is involved in the carcinogenesis and tumor metastasis of prostate cancer with increased expression correlating with higher cell proliferation rate and lower apoptosis (programmed cell death).
SRD5A2: “Steroid 5-alpha reductase type II” codes for the enzyme that converts testosterone to DHT (the activated form); genotypes associated with lower levels of activity are more common in populations at low risk for prostate cancer. This is the very enzyme blocked by finasteride and Dutasteride and why these medications can mitigate risk for prostate cancer.
CELLULAR ORGANIZATION GENES
FLNC: “Filamin-C” is a protein coded by genes that are highly expressed and amplified in prostate cancer cells and promote prostate cancer cell migration.
GSN: “Gelsolin,” a component of semen, induces apoptosis of activated lymphocytes in prostate cancer and when the gene is highly expressed in prostate cancer cells is associated with tumor progression, recurrence, metastasis, and poor prognosis.
GSTM2: “Glutathione S-transferase Mu” is a tumor suppressor gene that when silenced by hypermethylation promotes prostate cancer progression.
TPM2: “Beta-tropomyosin” is a member of the actin filament binding protein family. Mutations in this gene leading to decrease expression can lead to loss of the stable actin microfilament organization that is associated with prostate cancer cell transformation.
STROMAL RESPONSE GENES
BGN: “Biglycan” is a proteoglycan of extracellular matrix and when expressed is associated with prostate cancer aggressiveness.
COL1A1: “Collagen type I alpha 1” is an oncoprotein the production of which is upregulated in prostate cancer.
SFRP4: “Secreted frizzled-related protein 4” gene expression is associated with higher prostate grade and recurrent prostate cancer after surgery.
CELLULAR PROLIFERATION GENES
TPX2: “Xenopus kinesin-like protein 2” plays an important role in mitosis (the mitotic spindle) and promotes prostate tumor growth.
REFERENCE PATHWAYS
ARF1: “ADP-ribosylation factor 1.”
ATP5E: “ATP synthase F1 subunit epsilon.”
CLTC: “Clathrin Heavy Chain.”
GPS1: “G Protein Pathway Suppressor 1.”
PGK1: “Phosphoglycerate Kinase 1.”
