Plasma AR and abiraterone-resistant prostate cancer
A partir d'échantillons sanguins prélevés -à plusieurs étapes d'un traitement par abiratérone- sur des patients atteints d'un cancer de la prostate résistant à la castration, cette étude évalue l'intérêt d'une technique de séquençage à haut débit pour quantifier le nombre de copies du gène du récepteur des androgènes dans le plasma et, ainsi, détecter une résistance thérapeutique
Androgen receptor targeting is the cornerstone of prostate cancer treatment. Even when the tumors become “castration-resistant” or no longer sensitive to androgen deprivation, androgen signaling can still be effectively targeted by newer drugs such as abiraterone and enzalutamide, which also inhibit the androgen signaling axis. Romanel et al. analyzed tumor DNA samples from the blood of 97 patients with castration-resistant prostate cancer at different times during the course of treatment with abiraterone. Although some new mutations emerged during therapy, the authors found that androgen receptor amplifications were present from the beginning and correlated with abiraterone resistance, suggesting that detection of these amplifications should be useful for identifying abiraterone-resistant cancers before starting treatment.
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 , résumé, 2014