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Plasma AR and abiraterone-resistant prostate cancer.

Artikel i vetenskaplig tidskrift
Författare 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
Publicerad i Science translational medicine
Volym 7
Nummer/häfte 312
Sidor 312re10
ISSN 1946-6242
Publiceringsår 2015
Publicerad vid
Sidor 312re10
Språk en
Länkar dx.doi.org/10.1126/scitranslmed.aac...
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämnesord Adult, Aged, Aged, 80 and over, Androstenes, therapeutic use, DNA Copy Number Variations, Drug Resistance, Neoplasm, Humans, Male, Middle Aged, Point Mutation, Prostate-Specific Antigen, blood, Prostatic Neoplasms, Castration-Resistant, blood, drug therapy, genetics, Receptors, Androgen, blood, genetics, Young Adult
Ämneskategorier Klinisk medicin

Sammanfattning

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.

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