Phase II study of cytarabine in men with docetaxel-refractory, castration-resistant prostate cancer with evaluation of TMPRSS2-ERG and SPINK1 as serum biomarkers.
What's known on the subject? and What does the study add? 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.


OBJECTIVE
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.


METHODS
Ten of a planned maximum of 30 men received i.v. cytarabine at doses of 0.25-1g/m(2) 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.
Department of Medical Oncology, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada.
Neesha C
NC
Dhani
Urban
U
Emmenegger
Laurie
L
Adams
Jan
J
Jongstra
Ian F
IF
Tannock
Srikala S
SS
Sridhar
Jennifer J
JJ
Knox
John R
JR
Day
Jack
J
Groskopf
Anthony M
AM
Joshua
D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D002352:Carrier Proteins / Q000235:genetics*; D002369:Castration; D003561:Cytarabine / Q000627:therapeutic use*; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics; D012333:RNA, Messenger / Q000097:blood*; D012697:Serine Endopeptidases / Q000235:genetics*; D043823:Taxoids / Q000627:therapeutic use; D015534:Trans-Activators / Q000235:genetics*; D000071230:Transcriptional Regulator ERG; D014359:Trypsin Inhibitor, Kazal Pancreatic
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D015415:Biomarkers; D002352:Carrier Proteins; C072312:ERG protein, human; D012333:RNA, Messenger; C486642:SPINK1 protein, human; D043823:Taxoids; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D003561:Cytarabine; D000077143:Docetaxel; D014359:Trypsin Inhibitor, Kazal Pancreatic; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human