(image from NEJM)

Overview of Genes and Mutations

Your genes contain DNA, which carries instructions for every chemical process in your body. Literally, everything, including the color of your eyes to finding an ridding the body of cancer cells.  As your cells grow and divide, they make copies of their DNA and it’s not uncommon for some minor mistakes to occur.

Normal, healthy cells have mechanisms to recognize mistakes and repair them. But people who inherit one of the abnormal genes lack the ability to repair these minor mistakes. An accumulation of these mistakes leads to increasing genetic damage within cells and eventually can lead to the cells becoming cancerous.

The DNA can become mutated, meaning damaged, from what is inherited from your parents or environmental chemicals like radiation, and all sorts of different chemicals.

So, for instance, a gene called PTEN is supposed to protect your body from cancer cells. When this gene stops working, that can be one of the causes of cancer. Same with the BRCA gene and many others.

These are the main genes associated with potentially aggressive prostate cancer when mutated:

BRCA 2, BRCA 1 (BRCA 2 mutation is about 70% more significant in aggressive prostate cancer than BRCA 1), ATM CHEK2  BRCA1, RAD51D, PTEN, and PALB2.

On this post, I’d like to discuss material I lectured on to a group of naturopathic oncologist on February 17, 2019.

The focus was on how to use genetics ( and other tests) to better make decisions on what is next for men who may have (or diagnosed with) prostate cancer.

Here we go…

Testing Before a Prostate Biopsy

No man wants a biopsy. And many are unnecessarily done.

How can we determine who should undergo a prostate biopsy where, if we find it early, that person can be cured?

The first thing is to determine the genetic risk. One test that I know use for cancer is called COLOR.

The COLOR cancer genetic test looks at the following genetic mutations to determine the risk of cancer: (the bolded ones are specific to prostate cancer)

APC, ATM, BAP1, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A (p14ARF), CDKN2A (p16INK4a), CHEK2, EPCAM, GREM1, MITF, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, POLD1, POLE, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53

To order this genetic mutation test, speak with your physician.

Then there are the more prostate cancer-specific tests:

The 4K score

The 4K Score by OPKO is not a genetic test.

It measures four kallikreins (thus 4K): total PSA, free PSA, intact PSA and hK2.

Briefly, kallikreins are a group of proteins enzymes throughout the body. There’s at least 15 of them throughout the body. The prostate has two of them, hK2 and hK3 (PSA).

How to order a 4K Score? 4k Score is a blood test managed in office by the physician (blood draw, paperwork, and mailing of the specimen) or through Bioreference Labs. I don’t believe other major lab companies like Quest labs for Labcorp offer 4K at this time (02/17/19).

The Science on 4K

The 4K score has shown to help advise against biopsy in men with elevated PSA is a safe strategy.

What does the 4K Score tell you? If the 4Score is less than 7.5 that means there is very little likelihood one has aggressive prostate cancer and likely no biopsy needed.

Anything higher than 7.5 implies a higher likelihood of prostate cancer and it is variable

The Prostate Health Index (Phi)

Phi, an in an office blood test, is not a genetic test and includes total PSA, free PSA and −2proPSA using the following formula: ([−2]proPSA/fPSA) × √PSA.

Proenzyme PSA (proPSA) is a cancer-associated form of free PSA found primarily in the peripheral zone of the prostate, where 80% of prostate cancer occurs, as well as in the circulation.

What does the Phi score tell you? Phi score between 0 to 26.9 suggests a very low probability of significant prostate cancer. The higher the phi score the likelihood of serious prostate cancer. A phi score of 55 + suggests a 50% chance of aggressive disease. Phi is significantly a better marker for prostate cancer than PSA.

A comparative study from Sweden found that phi and the 4-kallikrein (4K Score) panel were equally helpful in improving the discrimination of high-grade prostate disease on biopsy.

How to order the Phi test? Phi is a blood test managed in office by a physician (blood draw, paperwork, and mailing of the specimen) or through AccuReference Labs. I don’t believe other major lab companies like Quest labs for Labcorp offer 4K at this time (02/17/19).

Select MDx

Select MDx is a genetic urine test.

A validated urinary three-gene panel (HOXC6, TDRD1, and DLX1) showed higher accuracy for significant prostate cancer.

What does the Select MDx score tell you? The results of the Select MDx reveal one of two things: Very low risk of prostate cancer, therefore, less need for biopsy or High Risk of prostate cancer, therefore a prostate biopsy may be needed.

How to order the Select MDx test? The test is done in an office and does not require a prostate massage prior to urine collection.

Testing After Prostate Biopsy

If a prostate biopsy is negative but one wants to confirm the results are a true negative, a Confirm MDx test can be performed.

What do I mean by a “true negative?”

Sometimes patients present with a high PSA but when a biopsy is performed the result is no cancer. The problem is there can be hidden prostate cancer the biopsy needle did not catch.

Confirm MDx

The Confirm MDx  is a genetic (really epigenetic) test that helps determine the likelihood of missed cancer in the prostate from a biopsy.

How to order the Confirm MDx test? The physician completes the requisition form, sends in for the pathology report to MDxHealth, and the prostate sample is sent in by the pathology lab where biopsy prostate tissue is stored.

What does Confirm MDx tell you? The results of the test tell you where there is what the company calls a “halo effect” indicating there is cancer that might have been missed somewhere in the prostate.

Confirm MDx is only for prostate tissue from biopsy that was shown to be negative (no cancer found) in the prostate.

After a Positive result for prostate cancer

Oncotype Dx by Genomic Health

The Oncotype is a genetic test that provides a Genetic Prostate Score (GPS) after prostate biopsy.

In studies performed at UCSF, this 17-gene signature was a reliable and helpful tool in assessing candidates for treatment or active surveillance without re-sampling or removing the entire prostate

The GPS is on a scale of 1-100, where higher scores are more suggestive of less than optimal pathology.   It is important to remember that a GPS score is a measurement of gene expression within prostate tumors and must be interpreted within the context of other relevant clinical factors.

In 395 prostate cancer patients with low and intermediate risk who underwent a radical prostatectomy was validated for its ability to predict men who have high-grade or high-stage prostate cancer at diagnosis and may help men diagnosed with PCa decide between active surveillance and immediate definitive treatment.

What does the Oncotype Dx tell you? The probability of more aggressive disease in the prostate, say, Gleason 7 (4 + 3) or higher,  that was not picked up by needle biopsy. The report provides a GPS score from 0 to 100. The lower the score, the less likelihood there is advanced prostate cancer somewhere in the prostate.

How to order the Oncotype Dx test? The physician completes the requisition form, sends in for the pathology report to and the prostate sample is sent in by the pathology lab where biopsy prostate tissue is stored.

Who qualifies for the Oncotype Dx?

Patients who have had a prostate biopsy within the last three years and had a positive result for prostate cancer with a low to intermediate grade disease – meaning, in general, a Gleason 6 or Gleason 7 (3+4).

Prolaris by Myriad Genetics

Prolaris is a genetic test showing expression of 31 genes involved in cell-cycle progression (CCP), an important regulatory step in the development of cancer.

A study examining the Prolaris panel in prostate biopsy specimens from 582 men with prostate cancer demonstrated that the test was a very strong predictor of later clinical outcomes including disease recurrence and progression to metastasis following surgery

What does the Prolaris test tell you? The probability of more aggressive disease in the prostate, say,  Gleason 7 (4 + 3) or higher, that was not picked up by needle biopsy. Also, the Prolaris test helps determine if patients are a candidate on active surveillance and the 10-year risk of developing metastasis following definitive treatment (prostatectomy or radiation. The report provides a Prolaris score which will fall between 0 and 10 with a higher score indicating more aggressive cancer. For every one unit increase in the Prolaris Score, the patient’s mortality risk doubles.

Who qualifies for the Prolaris test? Patients who have had a prostate biopsy within the last three years and had a positive result for prostate cancer with a low to intermediate grade disease – meaning, in general, a Gleason 6 or Gleason 7 (3+4).

How to order the Prolaris test? The physician completes the requisition form, sends in for the pathology report to Myriad, and the prostate sample is sent in by the pathology lab where biopsy prostate tissue is stored.

After a Prostatectomy

Decipher is a genetic test by GenomeDx Biosciences (Vancouver, BC, Canada) and Mayo Clinic (Rochester, MN, USA).

Decipher is used when the prostate is removed for prostate cancer then analyzed to determine the probability of recurrence and the risk of metastasis after prostatectomy.

To be clear, this test can only be used after the prostate is removed, not when any other treatment is performed.

A recent meta-analysis of five different studies examined the performance of Decipher to prognosticate the risk of metastases in 855 men with adverse pathology at the time of radical prostatectomy (RP).

What does the Decipher test tell you? Decipher generates a score between 0-1 in increments of 0.1. The close to one (1) the likelihood of recurrence or aggressive disease.

How to order the Decipher test? The physician completes the requisition form, sends in for the pathology report to the lab, and the prostate sample is sent in from where the prostate was removed. Details on ordering test here.

Prolaris by Myriad Genetics

Prolaris can also be used after prostatectomy.

What the test tells you and how to order is similar when testing biopsy tissue as explained above.