title: Plasma AR and abiraterone-resistant prostate cancer.
abstract: Androgen receptor (AR) gene aberrations are rare in prostate cancer before primary hormone treatment but emerge with castration resistance. To determine AR gene status using a minimally invasive assay that could have broad clinical utility, we developed a targeted next-generation sequencing approach amenable to plasma DNA, covering all AR coding bases and genomic regions that are highly informative in prostate cancer. We sequenced 274 plasma samples from 97 castration-resistant prostate cancer patients treated with abiraterone at two institutions. We controlled for normal DNA in patients' circulation and detected a sufficiently high tumor DNA fraction to quantify AR copy number state in 217 samples (80 patients). Detection of AR copy number gain and point mutations in plasma were inversely correlated, supported further by the enrichment of nonsynonymous versus synonymous mutations in AR copy number normal as opposed to AR gain samples. Whereas AR copy number was unchanged from before treatment to progression and no mutant AR alleles showed signal for acquired gain, we observed emergence of T878A or L702H AR amino acid changes in 13% of tumors at progression on abiraterone. Patients with AR gain or T878A or L702H before abiraterone (45%) were 4.9 and 7.8 times less likely to have a ≥50 or ≥90% decline in prostate-specific antigen (PSA), respectively, and had a significantly worse overall [hazard ratio (HR), 7.33; 95% confidence interval (CI), 3.51 to 15.34; P = 1.3 × 10(-9)) and progression-free (HR, 3.73; 95% CI, 2.17 to 6.41; P = 5.6 × 10(-7)) survival. Evaluation of plasma AR by next-generation sequencing could identify cancers with primary resistance to abiraterone.
authors.affiliation: Centre for Integrative Biology, University of Trento, Trento 38123, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Romanel
authors.affiliation: The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Delila
authors.initials: D
authors.lastname: Gasi Tandefelt
authors.affiliation: The Institute of Cancer Research, London SW7 3RP, UK. Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola 47014, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Conteduca
authors.affiliation: The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Jayaram
authors.affiliation: Centre for Integrative Biology, University of Trento, Trento 38123, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Casiraghi
authors.affiliation: The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Wetterskog
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola 47014, Italy.
authors.forename: Samanta
authors.initials: S
authors.lastname: Salvi
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola 47014, Italy.
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
authors.affiliation: The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK.
authors.forename: Zafeiris
authors.initials: Z
authors.lastname: Zafeiriou
authors.affiliation: The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Rescigno
authors.affiliation: The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK.
authors.forename: Diletta
authors.initials: D
authors.lastname: Bianchini
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola 47014, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Gurioli
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola 47014, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Casadio
authors.affiliation: The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Carreira
authors.affiliation: The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Goodall
authors.affiliation: The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Wingate
authors.affiliation: The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ferraldeschi
authors.affiliation: The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK.
authors.forename: Nina
authors.initials: N
authors.lastname: Tunariu
authors.affiliation: The Institute of Cancer Research, London SW7 3RP, UK.
authors.forename: Penny
authors.initials: P
authors.lastname: Flohr
authors.affiliation: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola 47014, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: De Giorgi
authors.affiliation: The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK.
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.affiliation: Centre for Integrative Biology, University of Trento, Trento 38123, Italy. Institute for Computational Biomedicine, Weill Cornell Medicine, NY 10021, USA. Institute for Precision Medicine, Weill Cornell Medicine, NY 10021, USA. demichelis@science.unitn.it gerhardt.attard@icr.ac.uk.
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.affiliation: The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK. demichelis@science.unitn.it gerhardt.attard@icr.ac.uk.
authors.forename: Gerhardt
authors.initials: G
authors.lastname: Attard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000736:Androstenes / Q000627:therapeutic use; D056915:DNA Copy Number Variations; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D017430:Prostate-Specific Antigen / Q000097:blood*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D011944:Receptors, Androgen / Q000097:blood / Q000235:genetics; D055815:Young Adult
chemical_list: C410798:AR protein, human; D000736:Androstenes; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen; C089740:abiraterone