To date, there has been limited impetus to examine the use of cytarabine in prostate cancer.
We presented preliminary laboratory data to suggest its utility in the castration refractory prostate cancer (CRPC) population which, combined with a previous case report, suggested it may have hitherto unrecognized utility in this setting. Embedded in this study was peripheral blood sampling for TMPRSS2-ERG and SPINK1, two genes that are believed to define prostate cancer genotypes, to assess their utility as biomarkers This study suggests that at the delivered doses, cytarabine has limited efficacy and significant myelotoxicity suggesting, it does not have a role in the treatment of docetaxel-refractory CRPC. The presence of serum TMPRSS2-ERG and SPINK1 mRNA biomarkers recovered from blood suggest that their analysis is worthy of further study.
OBJECTIVES: To run a phase II clinical trial of cytarabine in men with docetaxel-refractory, castration-resistant prostate cancer (CRPC), based on evidence that cytarabine might be effective in men with abnormalities of ERG oncogenes. To measure mRNA levels of prostate cancer-related genes in blood as biomarkers.
PATIENTS AND METHODS: Ten of a planned maximum of 30 men received i.v. cytarabine at doses of 0.25-1g/m2 at 21-day intervals. The primary endpoint was prostate-specific antigen (PSA) response. Archival tumour samples were assessed by fluorescence in-situ hybridization for TMPRSS2:ERG translocation, and by immunohistochemistry for serine peptidase inhibitor Kazal type 1 (SPINK1). Blood was processed for mRNA quantification of TMPRSS2:ERG (exon1:exon4), SPINK1 and PSA.
RESULTS: A PSA response was not observed in any patient. The trial was stopped at the end of stage 1 of a modified Flemming design. The median number of cycles administered was 3. Grade 3-4 haematological toxicity was common. Five patients were subsequently excluded from the study for toxicity, and five for disease progression. Analysis of whole blood mRNA for T1:E4 translocation in TMPRSS2:ERG was consistent with that in the tumour in 8/9 evaluable cases (one was concordantly positive, seven were concordantly negative), SPINK1 results were concordant in 9/10 cases (two were concordantly positive, seven were concordantly negative [P= 0.047 for the predictive value]). There was no correlation between PSA or SPINK protein and their respective mRNA copy levels in blood.
CONCLUSIONS: Cytarabine at the doses used is ineffective for men with CRPC. Blood mRNA levels of prostate cancer genes may represent a novel aspect of monitoring prostate cancer and have implications for the understanding of tumour-derived mRNA.
Written by:
Dhani NC, Emmenegger U, Adams L, Jongstra J, Tannock IF, Sridhar SS, Knox JJ, Day JR, Groskopf J, Joshua AM. Are you the author?
Department of Medical Oncology, Princess Margaret Hospital, University Health Network Odette Cancer Centre, Sunnybrook Health Sciences Centre Genetics and Development Division, Toronto; Western Research Institute, University Health Network, Toronto Western Hospital, Toronto, ON, Canada; Gen-Probe Inc, San Diego, CA, USA.
Reference: BJU Int. 2012 Feb 7. Epub ahead of print.
doi: 10.1111/j.1464-410X.2011.10922.x
PubMed Abstract
PMID: 22313860
