Cell free DNA (cfDNA) and circulating tumor DNA (ctDNA) have gained prominence as a target for personalizing CRPC therapy. cfDNA is found free floating in the circulation and is higher in men with cancer compared to healthy controls. Specifically, ctDNA may constitute <1%-90% of the total cfDNA. Furthermore, genomic changes in ctDNA are detectable in mCRPC patients, including mutational gains/losses and rearrangements. Clinically, this information has been extrapolated to mutations in the androgen receptor, allowing development of a biomarker for therapeutic resistance to mCRPC treatment regimens.
In work form Dr. Chi’s group, they assessed 65 men with mCRPC commencing enzalutamide, obtaining baseline plasma and at 12 weeks and/or disease progression. They found that cfDNA profiles demonstrated androgen receptor and non-androgen receptor gene alterations correlated with PSA response >50% and progression free survival (PFS).1 Specific gene alterations implicated included RB1 loss, AR gain/amplification, MET gain/amplification, MYC gain/amplification, and AR mutation. In further work from Dr. Chi’s group (in press), when comparing 50 solid and liquid biopsies in these patients, a targeted panel revealed 71 somatic mutations in the solid biopsies, of which 100% were also identified in cfDNA.
When Dr. Chi’s group assessed the genomic landscape of 115 men in a sequencing study of abiraterone vs enzalutamide, numerous genes were identified with prognostic implications. These genes include AR amplification (56.5%), AR mutation (12.2%), p53 alteration (56.5%), RB1 alteration (28.7%), PI3K pathway mutations (49.6%), BRCA2 or ATM somatic mutation (5.2%), BRCA2 or ATM germline mutation (4%), and SPOP mutations (10.4%). On multivariate analysis, BRCA2/ATM truncating mutation (HR 5.34, 95%CI 2.84-10.03), p53 inactivation (HR 2.21, 95%CI 1.38-3.55), and PI3K pathway mutations (HR 1.95, 95%CI 1.31-2.90) were significant for time to progression.
Finally, Dr. Chi outlined two ongoing, exciting clinical trials in this space. CCTG.IND.223 is a phase II study of the CDK4/6 inhibitor palbociclib in mCRPC patients with and without cyclin D1 amplification in ctDNA. Patients with mCRPC and prior treatment will have ctDNA genome sequencing to assess cyclin D1 status and then receive palbociclib until progression. Second, a Canadian Cancer Trial Group (CCTG) umbrella trial will sequence men with mCRPC who will then receive one of a number of different treatment options (see Figure).
Dr. Chi concluded with a number of summary points regarding ctDNA in mCRPC patients. First, ctDNA is abundant and representative of the mutational landscape of mCRPC. Second, detection of genomic aberrations is correlated with outcomes in cohorts of CRPC patients treated with abiraterone and enzalutamide. Third, the liquid biopsy approach is minimally invasive and permits genomic classification and serial evaluations. Finally, the CCTG umbrella trial will test the clinical utility of ctDNA to select mCRPC patients for targeted therapy.
Presented By: Kim Chi, MD, BC Cancer Agency, Vancouver Prostate Centre, Vancouver, BC, Canada
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre Twitter: @zklaassen_md at the 72nd Canadian Urological Association Annual Meeting - June 24 - 27, 2017 - Toronto, Ontario, Canada
References:
1. Wyatt AW, Azad AA, Volik SV, et al. Genomic Alterations in Cell-Free DNA and Enzalutamide Resistance in Castration Resistant Prostate Cancer. JAMA Oncol 2016;2(12):1598-1606.c/astration resistant prostate cancer (CRPC)