Predictive molecular markers for colorectal cancer patients with resected liver metastasis and adjuvant chemotherapy.
OBJECTIVE
The aims of the study were to evaluate the predictive value of 8 candidate molecular markers for colorectal cancer (CRC) patients receiving hepatic arterial infusion (floxuridine [FUDR] and dexamethasone) and systemic irinotecan (CPT11) post resection of liver metastasis.


METHODS
RNA was extracted from microdissected tumor cells of fixed and embedded specimens of resected liver metastases (94 cases) and analyzed by quantitative reverse-transcription polymerase chain reaction (RT-PCR) for thymidine phosphorylase, dihydropyrimidine dehydrogenase, thymidylate synthase, uridine phosphorylase, uridine/cytidine (monophospho)kinase, Bcl-2 related protein, Cyclin-D1, and Survivin expression. Uni- and multivariate statistical analyses and an explorative hierarchical clustering analysis of quantitative RT-PCR data were performed for overall survival and recurrent disease.


RESULTS
After adjustment for multiple clinicopathologic parameters, none of the markers were significantly associated with overall survival (except, marginally, Cyclin-D1; P = .06) or extrahepatic recurrence. However, high Survivin (P = .03) and Cyclin-D1 (P = .05) levels were predictive for hepatic recurrence. Hierarchical cluster analysis identified 7 of 94 patients associated with lower hepatic recurrence (P < .001). This patient group was characterized by low Cyclin-D1 and Survivin messenger RNA levels, both genes also clustering together.


CONCLUSIONS
Cyclin-D1 and Survivin messenger RNA analyzed by standardized, quantitative RT-PCR are predictive markers for CRC patients receiving hepatic arterial infusion (FUDR/dexamethasone) and systemic CPT11 post resection of liver metastasis. Moreover, our exploratory hierarchical cluster analysis of quantitative RT-PCR data supports its potential as an application to define clinically relevant patient subgroups.
Lassmann
Silke
S
Institute of Pathology, University Hospital, Albert-Ludwigs University Freiburg, Freiburg, Germany. silke.lassmann@uniklinik-freiburg.de
Tang
Laura
L
Capanu
Marinela
M
Brabletz
Thomas
T
Schöpflin
Anja
A
Zur Hausen
Axel
A
Gonen
Mithat
M
Kemeny
Nancy
N
Shia
Jinru
J
Klimstra
David
D
Werner
Martin
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000097:blood*; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000473:pathology / Q000601:surgery; D005260:Female; D006801:Humans; D007261:Infusions, Intra-Arterial; D008113:Liver Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000556:secondary / Q000601:surgery; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor