Inexpensive screening for germline mutations to personalize treatment

Pritchard et al. last year discovered that certain rare germline mutations that interfere with DNA-repair mechanisms occur with greater than expected frequency in men with aggressive prostate cancer. A "germline mutation" means that it is inherited from one's parents and is part of a man's normal genetic profile, for better or worse. By contrast, a "somatic mutation" means that it occurs only in tumor tissue and not necessarily in normal cells. There are several genes responsible for repair of our DNA. Their job is to fix random replicative errors as they crop up, and to cause cells that cannot be repaired to commit suicide (apoptosis) before they can become cancerous. When our inherited germline DNA repair genes are faulty, cancers may appear at any time and grow unchecked. They also can result in radio-toxicity because healthy cells can't fix the X-ray damage to their DNA and die off en masse. This is the case for ATM and ATR mutations that occur in both copies of the inherited genes (called "bi-allelic") When tumor DNA repair is faulty, as it often is, the cells become immortal, DNA errors proliferate and lead to such phenomena as EMT (cells able to exist outside of the prostate and migrate easily), castration resistance, and drug resistance.

The table below shows the incidence of several of the most important DNA-repair genes and their prevalence (1) in men with metastatic prostate cancer (2) in men with localized prostate cancer, and (3) in men in the general population who don't have prostate cancer. About 1 in 8 (12%) men who have detected metastases have a germline DNA repair defect. That falls to only about 1 in 22 men who have localized prostate cancer, and 1 in 37 men without prostate cancer.

It is only worth knowing about if there is something we can do about it. Someday we may have gene editing tools that can correct those aberrations throughout the body. CRISPR and Zinc Finger technology are in their infancy, and have only just started to be used in clinical studies for prostate cancer. The two medicines we have in our armamentarium against prostate cancer in those with germline DNA-repair defects are PARP inhibitors (e.g., olaparib, rucaparib, talazoparib, etc.) and platinum-based chemotherapy (e.g., carboplatin, oxaliplatin, etc.). (Update Oct. 2019) Recent trials suggest that only those with the BRCA1/2 mutations (and maybe CHK2) respond to current PARP inhibitors see this link).

Color Genomics

Color Genomics is a division of Genome Dx, the same company that offers the Decipher test. They are now offering a 30-gene panel listing the most frequently observed mutations in DNA-repair genes. It includes all of the genes listed in the table above plus other genes that have been implicated in other cancers (see the list here). They also look for aberrant TP53 and PTEN - two gene mutations that have been implicated in the loss of tumor suppression and loss of apoptosis, and are prognostic for aggressive prostate cancer variants. What is astounding is the price -- only $249! A full genomic analysis of BRCA2 would cost somewhere between $2,000 to $3,000. By limiting  their analysis to the most common site mutations, they are able to make it affordable, albeit not as thorough. It can be ordered by a physician (they will provide one if necessary). It is a simple saliva test that the patient mails in, and genetic counseling is included with the results.

(Update) The Color Genomics test is available free of cost to men who have a diagnosis of prostate cancer - they are building a registry database.  Interested patients can obtain it by putting their contact info in the website below. They mail a saliva test kit and pay for the return postage.

https://www.prostatecancerpromise.org/

Associated with other indicators of poor prognosis

A team at Johns Hopkins reported on their use of the Color Genomics test in 150 patients to determine whether germline DNA-repair defects were associated with two rare and aggressive prostate cancer variants: ductal and intraductal prostate cancer. They also looked for associations with lymphovascular invasion discovered at pathology. Velho et al. reported:

• Ductal/intraductal histology was discovered in 48% who had the defects vs only 12% who were free of those defects.
• Lymphovascular invasion was discovered in 52% who had the defects vs. only 14% who were free of those defects.
• 44% of patients with a positive germline test would not have been offered genetic screening according to current National Comprehensive Cancer Network (NCCN) guidelines. (update note: NCCN has changed its guidelines)

Other tests

While 23andMe offers a germline test that the consumer can order without a doctor, it is inferior. There are, say, 10,000 or more genetic mutations that can occur within a single BRCA2 gene. 23andMe only looks at a narrow pre-defined range of genomic abnormalities, using a silicon SNP array. Color Genomics uses "next generation sequencing" to look at many more types of genomic aberrations. There are other tests available from AmbryGenetics and Myriad.

Those who test positive may wish to investigate a clinical trial of a PARP inhibitor:

• Olaparib (multiple US & Int'l locations)
• Niraparib + Zytiga vs Zytiga alone for mCRPC -multiple locations
• Olaparib + Keytruda (cohort A) mCRPC- multiple locations
• Olaparib + durvalumab recurrent - Memorial Sloan Kettering
• Olaparib + abiraterone - multiple sites
• Olaparib+ AZD6738 (ATR inhibitor) - U Mich
• Rucaparib (Phase 2) mCRPC - multiple sites
• Rucaparib +abiraterone or enzalutamide - sites TBD
• Rucaparib vs Zytiga/Xtandi/Taxotere(Phase 3) mCRPC - multiple sites
• Niraparib mCRPC - multiple sites
• Bavencio (PD-L1 inhibitor) + Talazoparib -mCRPC -multiple sites
• BGB-290 + Temozolomide - locally advanced/metastatic - multiple sites
• Olaparib + Xofigo -mCRPC - UCSD & Ohio State U
• Olaparib - recurrent - Baltimore, Omaha, Phila & Pittsburgh
• Jevtana, carboplatin then olaparib - aggressive variants - MD Anderson
• Talazoparib + Zytiga/Xtandi - mCRPC - multiple locations
• Talazoparib + Avelumab -locally advanced/metastatic - NY & AZ
• Talazoparib - mCRPC - multiple locations
• Rucaparib -mHSPC & ADT-naive- Johns Hopkins
• Rucaparib + carboplatin + docetaxel - mCRPC (allows somatic mutations)- UWashington Seattle
• Rucaparib - germline or somatic- UOP

Carboplatin trials specifically for men with DNA-repair defects:

• Docetaxel + Carboplatin - mCRPC - VA Hospitals, LA & Puget Sound
• Docetaxel + Carboplatin - mCRPC - UWashington Seattle
• Carboplatin - mCRPC - Zurich
• Carboplatin - mCRPC - UK

Most (7 out of 8) metastatic patients will learn nothing from this test and it will be a waste of money. But for some who seem to have an unusually aggressive prostate cancer variant, have ductal/intraductal histology, or have had lymphovascular invasion identified at pathology, it may be worth paying for the relatively inexpensive test. It may indicate that a platin may be a preferred form of chemo, or that a clinical trial of a PARP inhibitor may be warranted.