PCa Commentary | Volume 152 – April 2021

Posted by Edward Weber | April 2021

GENOMIC SEQUENCING and GENOMIC CLASSIFIERS: Aids to Decision Making.

A primer just to provide a ‘heads-up’.

Genomic classifier panels for risk stratification and whole-genome sequencing in search of actionable mutations both provide personal molecular data that can guide management decisions. However, each provides an entirely different category of information. Both are assayed on tissue from the surgical prostate specimen or a prostate biopsy.

Genomic Sequencing

Genome sequencing for germline (inherited) mutations is usually performed in the pathology department that the urologist associates with or sent to a commercial laboratory such as Foundation One, Guardant360 or Myriad Genetics. The resulting report cites the several hundred mutations that were assessed, what mutations were found and often suggests applicable drugs or relevant clinical trials addressing that mutation. Commercial laboratories also offer specific liquid assays for mutations in the BRCA family of mutation (performed on plasma assaying circulating tumor DNA). FoundationOne Liquid Cdx and Guardant360 Cdx are two examples of BRCA-family mutation assays.  

Currently ‘actionable’ mutations (i.e. ones for which there are specific treatments available) are limited to mutations in the BRCA family (BRCA 2, BRCA 1, ATM, PALB2, CHEK2, CDK12, etc.). These occur in 8 – 10% of primary tumors and in ~ 20% – 25% of men with mCRPC. These mutations impede DNA damage repair and offer benefit from treatment with PARP inhibitors, such as Olaparib or Rucaparib. 

mMMR is a rare mutation seen in 2% – 4% of men with mCRPC. When mutated, MMR confers a sensitivity to immune checkpoint inhibitors. 

A new subtype of prostate cancer wherein both copies of the gene CDK2 have been lost can respond to immune checkpoint inhibitors (Wu et al.,Int.J.Can oder, Jan 2020).

Who Should be Tested and When:

The National Cancer Cooperative Network (NCCN) recommends germline sequencing for men with a strong family history of prostate cancer, regional lymph node spread, high-risk and metastatic disease. Men diagnosed with the rare ductal cancer should be tested, since nearly half carry an actionable DNA damage repair mutation (Schweizer et al. JCO Precision Oncology, 2019).  

Although a man’s initial treatment may not be influenced by discovered mutations, the information may be relevant in choosing the early sequencing of treatments. Later in a man’s disease course under the pressure of therapy new mutations (somatic) may arise. These can be diagnosed by a biopsy of a metastatic site, but more easily and safely can be assayed in blood plasma for circulating tumor DNA (ctDNA). These mutations may suggest alternative treatment options or applicable clinical trials.

Genomic Classifiers:

Genomic classifiers are panels of genes selected to assess a cancer’s aggressiveness expressed as the likelihood of metastases in 5 to 10 years. The tests are performed on tissue from the prostate specimen or a prostate biopsy. Three commonly used classifiers are OncotypeDx (Exact Sciences); Prolaris (Myriad Genetics) and Decipher (Decipher Bioscience). Each has been extensively validated and is covered by Medicare for localized disease at diagnosis. The classifiers have been developed to supplement, and potentially improve, the risk assessment based on the standard set of tools, i.e., Gleason score, PSA, PSA Density,  and personal characteristics (i.e., the  CAPRA score).  

CAPRA (Cancer of the Prostate Risk Assessment) score is comprised of the PSA, Gleason score, clinical stage (i.e., T1c), number of positive biopsy cores and age. (Google “How to calculate (and use) your CAPRA score.”). The CAPRA score is a risk assessment tool and is figured into the reports of the genome classifiers.

The classifiers are especially informative for men diagnosed with intermediate-risk cancer, a widely heterogeneous grouping, commingling various subtypes of histology and adverse features (i.e., perineural invasion, extracapsular extension, abundant positive biopsy cores ). This intermediate-risk group, now subdivided into ‘favorable’ and ‘unfavorable,’ includes a diverse mix of molecular behaviors which are not fully characterized by their appearance under the microscope or by the usual clinical parameters. The classifiers can occasionally reclassify (upgrade) some Gleason 3+3 cancers exhibiting unfavorable features and also unexpectedly downgrade the risk of a modest number of high-risk cancers.

A genomic classifier can offer additional management guidance in three commonly encountered scenarios: 

1. for men with Gleason 3 + 4 or Gleason 3 + 3 with worrisome features who might be under consideration for active surveillance (Kim et al., Prostate Cancer and Prostate Diseases, 22,  2019),
2. in deciding on the need for salvage radiation therapy following prostatectomy (Morgan et al., JCO 39,no. 6 Feb 2021) and
3. in deciding whether ADT is beneficial after radiation for men with PSA recurrence following prostatectomy (Feng, Genitourinary Cancers Symposium 2020, Feb 2020)

An example:  Clinical trial RTOG 9601 was a randomized study of radiation with or without anti-androgen therapy in recurrent prostate cancer following surgery. The men had advanced localized disease. Half received ADT compared to placebo. The surgical specimen was evaluated by Decipher. In an analysis of the trial results by Dr. Feng (Assoc. Prof. Radiation Oncology, UCLA) presented at ASCO GU 2020 showed that “The absolute benefit from hormone therapy is smaller in the low Decipher risk groups.”  This study suggests that patients who have low Decipher risk scores could potentially be spared from receiving ADT and avoid the associated toxicity.

Details for the Three Genomic Classifiers:

Decipher:  Decipher assesses 22 RNA biomarkers and reports a Decipher score ranging from 0 to 1.0 to predict (1) the 5-year probability of metastases, and (2) the 10-year probability of cancer specific mortality. A score of <0.45 is classified as low-risk; a score of >0.6, high-risk.  An example: For a man following a prostatectomy whose score was 0.36 Decipher would predict a 2.3 % risk of metastases in 5 years and the risk of prostate cancer mortality of 3.1% at 10 years.

Prolaris:  Prolaris assesses 46 genes involved in cancer cell proliferation and predicts cancer aggressiveness in terms of the risk of developing metastases at 10 years. The test results are scaled between 0 and 5. A high-risk threshold is set at above 2.112, below which the 10-year risk of metastases decreases from 4.2% .

Oncotype Dx Prostate Cancer: Oncotype Dx is a 17-gene RNA based predictive biomarker panel assessing the aggressiveness of a cancer. The Genomic Prostate Score (GPS) Report indicates the percentage likelihood of metastases and prostate cancer death in 10 years. The recurrence score ranges from 0 – 100 with < 20 being very favorable (no metastases in 10 years). The GPS also predicts the likelihood of having adverse pathology, i.e. Gleason > 4+3 and/or stage pT3 at prostatectomy.

Based on the risk prognosis resulting from a classifier the physician and patient have the responsibility of deciding how to integrate the information into a personalized management decision. 

BOTTOM LINE:

The information provided by genomic sequencing and genomic classifiers now permit incorporating the unique molecular characteristics of a man’s cancer in decision-making regarding an individualized treatment plan.

“I want to thank Dawn Scott, Staffperson, Tumor Institute Radiation Oncology Group, & Mike Scully, Librarian, Swedish Medical Center for their unfailing, timely, and resourceful support of the Commentary project. Without their help this Commentary would not be possible.”