Circulating Tumor Cells Provide Information Leading to Liquid Biopsy Biomarkers

Genomic analysis of pooled circulating tumor cells (CTCs) from men with metastatic castration-resistant prostate cancer revealed a reproducible, but highly complex pool of potential molecular biomarkers.

Metastatic castration-resistant prostate cancer (mCRPC) is the type of prostate cancer that does not respond to androgen deprivation or treatment with androgen receptor antagonists.

Investigators at Duke University (Durham, NC, USA) turned to CTCs as a source of genetic information with the potential to facilitate a greater understanding of tumor biology and enable a more precise approach to treatment. Towards this end, they analyzed and compared the genomes from matched CTCs and normal leukocytes obtained from 16 patients with mCRPC and primary or acquired resistance to the drug abiraterone acetate or enzalutamide.

Abiraterone acetate is a steroidal androgen synthesis inhibitor used in combination with prednisone in mCRPC. It is a prodrug to the active agent abiraterone, which has the capacity to lower circulating testosterone to an undetectable level. Enzalutamide is a synthetic non-steroidal anti-androgen used for the treatment mCRPC. This drug was reported to reduce serum prostate specific antigen (PSA) levels by 89% after a month of treatment.

CTCs and paired leukocytes were isolated from blood through red cell lysis, CD45 depletion, and flow sorting based on expression of the EpCAM/CD45 surface marker. The investigators performed whole genomic copy number analysis of CTCs and matched patient leukocytes using array-based comparative genomic hybridization (aCGH) and 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.

Results revealed genomic gains in more than 25% of CTCs. Gains were observed in the AR, FOXA1, ABL1, MET, ERG, CDK12, BRD4, and ZFHX3 genes. Common genomic losses involved the PTEN, ZFHX3, PDE4DIP, RAF1, and GATA2 genes.

“We have developed a method that allows us to examine the whole genome of rare circulating cancer cells in the blood, which is unique in each patient, and which can change over time during treatment,” said senior author Dr. Andrew Armstrong, professor of medical oncology at Duke University. “Among the genomic changes in the patients’ individual cancers, we were able to find key similarities between the cancer cells of men who have hormone-resistant prostate cancer. Our goal is to develop a liquid biopsy that would be non-invasive, yet provide information that could guide clinical decisions.”

The study was published in the September 6, 2016, online edition of the journal Clinical Cancer Research.

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