Whole genomic copy number alterations in circulating tumor cells from men with abiraterone or enzalutamide resistant metastatic castration-resistant prostate cancer
A partir d'échantillons sanguins prélevés sur 16 patients atteints d'un cancer métastatique de la prostate résistant à la castration, cette étude évalue les performances d'une technique d'analyse du génome des cellules tumorales circulantes pour identifier des anomalies du nombre de copies de certains gènes en association avec une résistance à l'enzatumalide ou l'abiratérone
Purpose: Beyond enumeration, circulating tumor cells (CTCs) can provide genetic information from metastatic cancer that may facilitate a greater understanding of tumor biology and enable a precision medicine approach.
Experimental design: CTCs and paired leukocytes from men with metastatic castration-resistant prostate cancer (mCRPC) were isolated from blood through red cell lysis, CD45 depletion, and flow sorting based on EpCAM/CD45 expression. We next performed whole genomic copy number analysis of CTCs and matched patient leukocytes (germline) using array-based comparative genomic hybridization (aCGH) from 16 men with mCRPC, including longitudinal and sequential CTCs aCGH analyses in the context of enzalutamide therapy.
Results: All patients had mCRPC and primary or acquired resistance to abiraterone acetate or enzalutamide. We compiled copy gains and losses, with a particular focus on those genes highly implicated in mCRPC progression and previously validated as being aberrant in metastatic tissue samples and genomic studies of reference mCRPC datasets. Genomic gains in >25% of CTCs were observed in AR, FOXA1, ABL1, MET, ERG, CDK12, BRD4, and ZFHX3, while common genomic losses involved PTEN, ZFHX3, PDE4DIP, RAF1, and GATA2. Analysis of aCGH in a sample with sequential enzalutamide resistant visceral progression showed acquired loss of AR amplification concurrent with gain of MYCN, consistent with evolution toward a neuroendocrine-like, AR-independent clone.
Conclusions: Genomic analysis of pooled CTCs in men with mCRPC suggests a reproducible, but highly complex molecular profile that includes common aberrations in AR, ERG, c-MET, and PI3K signaling during mCRPC progression, which may be useful for predictive biomarker development.
Clinical Cancer Research , résumé, 2015