1. >20% of mCRPC have defects in DNA repair genes – ie BRCA 1/2, ATM, MSH2, MSH6, etc.1
2. 12% of men with advanced PCa has germline mutations in DNA repair genes. This was irrespective of family history and age of onset. BRCA2 was most common, but there were numerous that accounted for just 1-2% of that 12%. 2
Based on this, he feels that failing to genetic test our patients is a disservice!
Dr. Cheng had highlighted who to test, including the recent NCCN guidelines. However, Dr. Sartor notes that the NCCN guidelines recommend testing for BRCA1, BRCA2, PALB2, ATM, and FANCA in these advanced PCa patients – but he is not sure why they limited it to these genes. His clinic currently uses panel testing – but they remain “hyper-aware” of out of pocket expenses to the patient.
- ASCO 2017 – Nicolosi et al. noted that 2017 NCCN genetic screening guidelines missed 37% of germline mutations
- Testing for only those genes listed above missed > 50%!
Cascade testing – if a test is positive, testing of family members is an OBLIGATION, not an option. It is tedious, time-consuming – but rewarding.
He next moved to current clinical management and how genetic testing may play a role.
At this time, AR axis targeting remains the mainstay of management. Despite the development of resistance, efficacy is still high enough that AR-targeted therapies are still the most commonly used. But, what to do when these fail?
Liquid biopsy of AR axis – circulating tumor DNA, CTCs and their contents may help overcome the heterogeneity of tumor samples. While they have predictive power, are they useful? Sometimes… but often not in the first line setting. More work is needed to help improve their utility.
- Recent work has found that amongst AR altered patients, there were mutations in 74 other genes – so AR alone isn’t the entire story!
- Certain AR mutations are associated with non-androgen activations and may account for resistance to AR-targeted therapies
1. DNA repair mutations – Platinum chemotherapy and PARP inhibitors may be appropriate in these patients, and phase III clinical trials are ongoing.
2. Immunotherapies / I/O’s
- biomarkers such as PD-L1, MSI, MMR, tumor mutational burden, etc.
- Yet, while pembro was pan-cancer approved for MSI high and MMR deficient patients, most of these are still being validated
He briefly reviewed some of the ongoing work in this area and some early results. Ultimately, despite certain signals of benefit, more biomarker work is needed!
This was a nice middle talk on practical approach. Still not a perfect science, but work is ongoing Upcoming clinical trial results will be critical to patient selection. At this time, platinum therapy and PD-1 inhibitors are his treatment of choice – but biomarkers are not yet useful.
Presented by: A. Oliver Sartor, MD, Tulane Medical School
References:
1. Robinson D, Van Allen EM, et al. Integrative Clinical Genomics of Advanced Prostate Cancer, Cell, 2015
2. Pritchard et al, Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer, NEJM, 2016
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA