Abstract 2959: Analysis of circulating tumor DNA reveals genomic alterations in metastatic prostate cancer patients treated with abiraterone acetate plus prednisone or enzalutamide
Authors: Jelena Belic, Ricarda Graf, Thomas Bauernhofer, Yauheniya Cherkas, Ulz Peter, Julie Waldispuehl-Geigl, Samantha Perakis, Michael Gormley, Jaymala Patel, Weimin Li, Jochen B. Geigl, Denis Smirnov, Ellen Heitzer, Mitchell Gross, Michael R. Speicher
Journal: Cancer Research (2018)

Abstract Background: Recent progress in the analysis of cell-free circulating tumor DNA (ctDNA) now allows for the monitoring of tumor genomes by noninvasive means. The introduction of abiraterone and enzalutamide for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients has led to a survival benefit. We analyzed genomic alterations as potential causes of disease progression using ctDNA in patients treated with abiraterone and enzalutamide. Furthermore, we investigated the correlation between cancer-associated clinical markers and the ctDNA detection in mCRPC patients. Patients and Methods: In order to identify variables associated with ctDNA detection, we analyzed two cohorts including 94 plasma samples from 25 treatment courses (23 patients) and 334 plasma samples from 125 patients, respectively. We performed low-pass whole-genome sequencing (plasma-Seq) for genome-wide profiling of somatic copy number alterations (SCNAs) and targeted resequencing of 31 prostate cancer-associated genes. Results: Applying plasma-Seq with targeted AR analyses we were able to identify significant genomic alterations in 16 of 25 (64%) cases in the first cohort. Our results indicated that AR amplification alone is not predictive for abiraterone and enzalutamide treatment outcome. In patients treated with abiraterone, low ctDNA levels at baseline were a significant determinant of progression-free survival. Next, we evaluated the determinants of ctDNA detection in an additional independent cohort of metastatic CRPC patients. Analysis of a total of 148 patients and 428 plasma samples from both cohorts revealed that increased levels of lactate dehydrogenase (LDH) highly correlated with the detection of ctDNA and could be used as the potential independent predictor of ctDNA release. Conclusion: Our results showed that AR amplification alone is an insufficient marker for the prediction of therapy response in patients treated with abiraterone and enzalutamide. Analyses of ctDNA in two independent cohorts have provided insights into unique patterns of response and the emergence of resistance to abiraterone and enzalutamide. Noninvasive analysis of ctDNA plays an important role in treatment monitoring and the prediction of therapy outcome in mCRPC patients. Citation Format: Jelena Belic, Ricarda Graf, Thomas Bauernhofer, Yauheniya Cherkas, Ulz Peter, Julie Waldispuehl-Geigl, Samantha Perakis, Michael Gormley, Jaymala Patel, Weimin Li, Jochen B. Geigl, Denis Smirnov, Ellen Heitzer, Mitchell Gross, Michael R. Speicher. Analysis of circulating tumor DNA reveals genomic alterations in metastatic prostate cancer patients treated with abiraterone acetate plus prednisone or enzalutamide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2959.