Heidi Fettke1, Edmond M Kwan2, Patricia Bukczynska3, Nicole Ng4, Tu Nguyen-Dumont5, Melissa C Southey6, Ian D Davis7, Andrew Mant7, Phillip Parente7, Carmel Pezaro8, Christine Hauser3, Arun A Azad9. 1. Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC, Australia. 2. Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC, Australia; Department of Medical Oncology, Monash Health, Clayton, VIC, Australia. 3. Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. 4. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. 5. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia; Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia. 6. Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia; Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia. 7. Medical Oncology Unit, Eastern Health, Box Hill, VIC, Australia; Eastern Health Clinical School, Monash University, Box Hill, VIC, Australia. 8. Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, England. 9. Department of Medicine, School of Clinical Sciences, Monash University, Clayton, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. Electronic address: arun.azad@petermac.org.
Abstract
Total plasma cell-free DNA (cfDNA) levels were recently shown to be prognostic in two large phase III trials of taxane chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). However, whether cfDNA concentration is predictive of treatment outcomes with androgen receptor pathway inhibitors (ARPIs) is unknown. We quantified plasma cfDNA levels at baseline (n = 74) and 4 weeks on treatment (n = 56) in a prospective cohort of mCRPC patients treated with the ARPIs abiraterone acetate or enzalutamide. Elevated total cfDNA concentration (log10) at both baseline (hazard ratio [HR] 5.5, p < 0.001) and week 4 (HR 7.5, p < 0.001) was a significant negative prognostic factor for overall survival (OS), a finding maintained after adjustment for plasma circulating tumour DNA fraction. Unexpectedly, a rise in cfDNA concentration from baseline to week 4 was also associated with significantly improved OS (HR 0.14, p = 0.003). Conversely, patients with ≥29.8% decrease in cfDNA from baseline (optimal cut-point) had significantly shorter median OS than the rest of the cohort (10.5 vs 25.7 mo, p = 0.03). Collectively, our findings point to the potential prognostic utility of quantifying cfDNA in mCRPC and in particular suggest that dynamic changes in total cfDNA levels may be a novel early predictive biomarker for therapeutic outcome in ARPI-treated patients. PATIENT SUMMARY: We measured the levels of total cell-free DNA (cfDNA) in the plasma of patients with metastatic prostate cancer prior to and 4 weeks after starting new hormonal drugs. We found that patients with higher levels of cfDNA or a higher proportion of tumour-derived DNA at baseline had worse outcomes on hormonal therapies. Similarly, higher levels of cfDNA at 4 weeks into therapy were also associated with worse outcomes. However, a rise in total cfDNA levels at 4 weeks compared with baseline was linked with better outcomes. Measuring changes in cfDNA concentration may be a useful and technically straightforward early way to predict how patients will respond to treatment in metastatic prostate cancer.
Total plasma cell-free DNA (cfDNA) levels were recently shown to be prognostic in two large phase III trials of taxane chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). However, whether cfDNA concentration is predictive of treatment outcomes with androgen receptor pathway inhibitors (ARPIs) is unknown. We quantified plasma cfDNA levels at baseline (n = 74) and 4 weeks on treatment (n = 56) in a prospective cohort of mCRPC patients treated with the ARPIs abiraterone acetate or enzalutamide. Elevated total cfDNA concentration (log10) at both baseline (hazard ratio [HR] 5.5, p < 0.001) and week 4 (HR 7.5, p < 0.001) was a significant negative prognostic factor for overall survival (OS), a finding maintained after adjustment for plasma circulating tumour DNA fraction. Unexpectedly, a rise in cfDNA concentration from baseline to week 4 was also associated with significantly improved OS (HR 0.14, p = 0.003). Conversely, patients with ≥29.8% decrease in cfDNA from baseline (optimal cut-point) had significantly shorter median OS than the rest of the cohort (10.5 vs 25.7 mo, p = 0.03). Collectively, our findings point to the potential prognostic utility of quantifying cfDNA in mCRPC and in particular suggest that dynamic changes in total cfDNA levels may be a novel early predictive biomarker for therapeutic outcome in ARPI-treated patients. PATIENT SUMMARY: We measured the levels of total cell-free DNA (cfDNA) in the plasma of patients with metastatic prostate cancer prior to and 4 weeks after starting new hormonal drugs. We found that patients with higher levels of cfDNA or a higher proportion of tumour-derived DNA at baseline had worse outcomes on hormonal therapies. Similarly, higher levels of cfDNA at 4 weeks into therapy were also associated with worse outcomes. However, a rise in total cfDNA levels at 4 weeks compared with baseline was linked with better outcomes. Measuring changes in cfDNA concentration may be a useful and technically straightforward early way to predict how patients will respond to treatment in metastatic prostate cancer.
Authors: Verena Lieb; Amer Abdulrahman; Katrin Weigelt; Siegfried Hauch; Michael Gombert; Juan Guzman; Laura Bellut; Peter J Goebell; Robert Stöhr; Arndt Hartmann; Bernd Wullich; Helge Taubert; Sven Wach Journal: Cells Date: 2021-11-18 Impact factor: 6.600