Abstract

Circulating tumor DNA fraction (ctDNA) as a surrogate predictive biomarker in metastatic castration-resistant prostate cancer (mCRPC).

Author
person Vincenza Conteduca Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, Italy info_outline Vincenza Conteduca, Daniel Wetterskog, Emanuela Scarpi, Alessandro Romanel, Giorgia Gurioli, Anuradha Jayaram, Cristian Lolli, Giuseppe Schepisi, Chiara Casadei, Cecilia Menna, Anna Wingate, Francesca Demichelis, Ugo De Giorgi, Gerhardt Attard
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Authors person Vincenza Conteduca Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, Italy info_outline Vincenza Conteduca, Daniel Wetterskog, Emanuela Scarpi, Alessandro Romanel, Giorgia Gurioli, Anuradha Jayaram, Cristian Lolli, Giuseppe Schepisi, Chiara Casadei, Cecilia Menna, Anna Wingate, Francesca Demichelis, Ugo De Giorgi, Gerhardt Attard Organizations Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, Italy, UCL Cancer Institute, LONDON, United Kingdom, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy, Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy, University College London Cancer Institute, London, United Kingdom, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy, University College London, London, United Kingdom, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy, Institute of Cancer Research and The Royal Marsden Hospital, Sutton, United Kingdom Abstract Disclosures Research Funding Other Background: Plasma ctDNA is a promising minimally invasive biomarker in mCRPC. Pre-treatment high levels of ctDNA reflect poor prognosis (Romanel et al, Sci Transl Med 2015; Annala et al, Cancer Discov 2018) . However, the role of plasma ctDNA in prostate tumour monitoring is largely unexplored. We aimed to determine if monitoring tumour response by quantifying ctDNA levels in plasma could enable early assessment of therapy efficacy for mCRPC. Methods: Between January 2011 and June 2016, 132 sequential plasma samples from 54 mCRPC patients (pts) (30 pre- and 24 post-chemotherapy) treated with abiraterone (abi) were collected. Targeted next-generation sequencing was performed on the PGM Ion Torrent using a 316 or 318 Chip to account for 1000X expected coverage per target. We estimated the global tumour content for each sequential plasma sample from study patients by using the approach developed in (Carreira et al, Sci Trasl Med 2014; Romanel et al, Sci Transl Med 2015 ) , which extends the CLONET framework (Prandi et al, Genome Biol 2014). Prostate Cancer Working Group -3 (PCWG3) criteria were used to assess clinical, biochemical (PSA) and radiographic (RAD) progression disease (PD). We considered ctDNA PD any increase of ctDNA from baseline value. Results: In our cohort of 54 pts (median age: 75 years, range 70-78), we observed 17 (31.5%) PD, 14 (25.9%) stable disease, and 23 (42.6%) partial/complete response after the first 3 months (mo) abi therapy. The odds ratio (OR) for PD having any increase in ctDNA and a PSA decline < 50% at ~3-mo therapy was 10.83, 95% CI 2.55-45.95, P = 0.001, and 3.27, 95% CI 0.89-12.3, P = 0.074, respectively. In addition, we assessed all 3 types of median PD time from starting abi treatment, suggesting the ability of ctDNA variation to predict overall PD [RAD PD = 6.8 mo, PSA PD = 4.4 mo, and ctDNA PD = 3.0 mo, P = 0.008). An increase of ctDNA levels during the first 3-mo abi treatment was significantly associated with a long-term androgen deprivation therapy (ADT) before plasma sample collection (previous ADT > 24 mo vs 12 > previous ADT ≤23 mo vs < 12 mo: P = 0.036). Conclusions: In mCRPC, an early change in ctDNA fraction may be considered as a predictive biomarker playing a key role in individualized disease monitoring. Prospective evaluation of treatment decisions based on ctDNA is now required.