ASCO GU 2019: Practical Application of Genomic Assays in Clinical Decision Making

San Francisco, CA (UroToday.com) Mark Rubin, MD presented on the practical application of genomic assays in clinical decision making in prostate cancer. Dr. Rubin began with a summarizing quote from a New-England Journal of Medicine paper published by Dr. Oliver Sartor1: “The use of advanced genomic analysis is now feasible to a greater extent than ever before. Whether its use improves treatment decisions is not yet clear…advanced genetics and immunology, two major drivers of progress in oncology, are not routinely incorporated into the care of patients with prostate cancer.”

In advanced prostate cancer, 5% of the patients have microsatellite instability or mismatch repair gene alterations, 10% have germline drug resistance mutations (DRM), and 20% have drug resistance mutations (somatic – germline). In genetic testing we count the germline sequence, in genomic testing, we count the tumor (somatic) sequence, and in the molecular imaging, we measure protein expression. There are numerous types of tests available for localized prostate cancer (Genomic Health, Myriad-CCP, Decipher, PCA3, and others). These usually predict some outcome or assess the risk of disease progression. In this presentation, Dr. Rubin had focused on assessing prostate cancer prognosis, and prediction.

Several important definitions that need to be mentioned include:
- A prognostic biomarker – is one that indicates an increased (or decreased) likelihood of a future clinical event, disease recurrence or progression in an identified population. Prognostic biomarkers are measured at a defined baseline, which may include a background treatment.
- A predictive biomarker is used to identify individuals who are more likely to respond to exposure to a particular medical product or environmental agent. The response could be a symptomatic benefit, improved survival, or an adverse effect.

The acquisition of samples for testing can be done using a buccal sample for germline DNA and control normal sample for genomics. It is also possible to use a tumor sample for tumor DNA/RNA/protein extraction for genomic sequencing, and transcriptomic sequencing. Lastly, it is possible to acquire tumor and normal DNA/RNA/protein fraction from a blood sample.

It has been shown that BRCA 1 and two mutations confer a more aggressive prostate cancer phenotype with a higher probability of nodal involvement and distant metastases.2 BRCA mutations are associated with poor survival outcomes, and this should be considered for tailoring clinical management of these patients. This has resulted in the development of a unique treatment strategy, targeting the DNA repair defect in BRCA mutant cells.3 Furthermore, it has been shown that DNA repair defects have a 30% response rate to PARP inhibitors, such as Olaparib.4 Interestingly, selected DNA repair germline mutations from the targeted panel and whole exome sequencing reveal 10-20% frequency in men with metastatic prostate cancer.5 A cross-sectional study demonstrated the results of  3607 men with a personal history of prostate cancer, who underwent germline genetic testing between 2013 and 2018, and was unselected for family history, stage of disease, or age at diagnosis.6 The results demonstrated that 37% of the patients with the positive variants that were detected, would not have been identified had they been tested using only the NCCN genetic/familial breast and ovarian guidelines (table 1). This resulted in the authors of this study concluding that the cost of genetic testing and counseling needs to be weighed against the cost of treating late stage cancer. The prevalence of mismatch repair gene mutations in prostate cancer patients has been shown to be 8.1%.7

Table 1: Detected variants in patients with a personal history of prostate cancer:
UroToday ASCOGU2019 Detected variants in patients with a personal history of prostate cancer
*Nicholsi P et al. JAMA ONCOL 2019

There are currently many tests available for genetic testing. We need a test that is designed to address clinically relevant alterations. For advanced prostate cancer, combining somatic and germline testing will be critical. Figure 1 demonstrates an overview of tests that are currently ready or regarded as promising.

Figure 1 – Tests that are ready or promising:
UroToday ASCOGU2019 Tests that are ready or promising

Androgen receptor (AR)-V7 has been found in <1% of hormone naïve prostate cancer (therefore it is not likely to be a useful biomarker at this stage) and appears only after resistance to androgen deprivation therapy (ADT). The differences in the prevalence of AR-V7 is likely due to different antibodies used. However, AR-V7 is expressed in 75% of progressing castrate-resistant prostate cancer. It is more expressed in tissue biopsy than in liquid biopsy. Heterogeneity is observed with implications for a partial response if some lesions have low AR-V7. Lastly, it is associated with resistance to AR-targeted agents but not to the taxane.

Dr. Rubin moved on to discuss the future for the diagnosis of castrate-resistant prostate cancer. A liquid biopsy will most likely overcome the limits of multiple metastases biopsies to capture heterogeneity and serial biopsies. There are currently several non-invasive methods being studied to monitor prostate cancer evolution. These include circulating tumor cells DNA, oncosomer and exosomes, and various forms of RNA. Plasma circulating tumor DNA (ctDNA) is abundant in progressing metastatic castrate resistant prostate cancer patients. Cell-free DNA (cfDNA) is shed by apoptotic normal and cancer cells. Putative ctDNA can be identified via somatic alteration in cfDNA, and ctDNA/cfDNA fractions are high in metastatic castrate-resistant prostate cancer but very variable (Figure 2). Changes in cfDNA concentrations correlate with both progression-free survival and overall survival in patients receiving first and second line taxane therapy and may serve as independent prognostic biomarkers of response to taxanes.8

Figure 2 – ctDNA correlation to disease progression:
UroToday ASCOGU2019 ctDNA correlation to disease progression

Dr. Rubin concluded his talk summarizing the tests that are ready for clinical use. The ones that need prospective validation include:
  1. Blood/biopsy/cfDNA DNA repair BRAC 1&2, atm
  2. CTC for AR-V7
  3. Metastatic biopsy – AR gain
  4. cfDNA for DNA fraction, AR, and others
Tests that have already been approved by the FDA include the MSI/MMR (multiple tests).  We hope that in the near future more tests will be able to give us prospectively validated results, which are clinically meaningful.

 
Presented by: Mark A. Rubin, MD, Professor, Principal Investigator, Director DBMR, The University of Bern, Switzerland

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

References:
  1. Sartor, O., & de Bono, J. (2018). Metastatic Prostate Cancer. New England Journal Of Medicine378(7), 645-657. doi: 10.1056/nejmra1701695
  2. Castro, E., Goh, C., Olmos, D., Saunders, E., Leongamornlert, D., & Tymrakiewicz, M. et al. (2013). GermlineBRCAMutations Are Associated With Higher Risk of Nodal Involvement, Distant Metastasis, and Poor Survival Outcomes in Prostate Cancer. Journal Of Clinical Oncology31(14), 1748-1757. doi: 10.1200/jco.2012.43.1882
  3. Farmer H et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005 Apr 14;434(7035):917-21.
  4. Mateo J. et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N Engl J Med. 2015 Oct 29;373(18):1697-708. doi: 10.1056/NEJMoa1506859.
  5. 5. Pritchard et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 2016; 375:443-453 DOI: 10.1056/NEJMoa1603144
  6.  Nicolosi, P., Ledet, E., Yang, S., Michalski, S., Freschi, B., & O’Leary, E. et al. (2019). Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines. JAMA Oncology. doi: 10.1001/jamaoncol.2018.6760
  7. Rodrigues DN et al. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. J Clin Invest. 2018;128(10):4441-4453. https://doi.org/10.1172/JCI121924.
  8. Mehra N et al.Plasma Cell-free DNA Concentration and Outcomes from Taxane Therapy in Metastatic Castration-resistant Prostate Cancer from Two Phase III Trials (FIRSTANA and PROSELICA)European Urology , Volume 74 , Issue 3, 283 - 291 Urol 2018