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.
Science translational medicine. 2015 Nov 04 [Epub]
Alessandro Romanel, Delila Gasi Tandefelt, Vincenza Conteduca, Anuradha Jayaram, Nicola Casiraghi, Daniel Wetterskog, Samanta Salvi, Dino Amadori, Zafeiris Zafeiriou, Pasquale Rescigno, Diletta Bianchini, Giorgia Gurioli, Valentina Casadio, Suzanne Carreira, Jane Goodall, Anna Wingate, Roberta Ferraldeschi, Nina Tunariu, Penny Flohr, Ugo De Giorgi, Johann S de Bono, Francesca Demichelis, Gerhardt Attard
Centre for Integrative Biology, University of Trento, Trento 38123, Italy. , The Institute of Cancer Research, London SW7 3RP, UK. , 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. , The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK. , Centre for Integrative Biology, University of Trento, Trento 38123, Italy. , 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. , Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola 47014, Italy. , The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK. , The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK. , The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK. , Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola 47014, Italy. , Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola 47014, Italy. , The Institute of Cancer Research, London SW7 3RP, UK. , The Institute of Cancer Research, London SW7 3RP, UK. , The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK. , The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK. , The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK. , 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. , The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK. , 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. The Institute of Cancer Research, London SW7 3RP, UK. The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK.