Background & Aims: 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.
Section snippets
Patients and Tissues
The study included resection specimens of liver metastases from 94 advanced stage CRC patients who had received HAI (FUDR/dexamethasone) in combination with systemic CPT11 post resection of liver metastasis.8 Previous chemotherapy of some patients was (1) immediately after diagnosis and resection of the primary CRC and before diagnosis of liver metastasis (adjuvant treatment 1) or (2) at the initial diagnosis of liver metastasis and before resection of liver metastasis (adjuvant treatment 2).
Patient Characteristics
The study included formalin-fixed and paraffin-embedded liver resection specimens of 94 CRC patients treated in a phase I/II trial with HAI (FUDR/dexamethasone) and systemic CPT11 postresection of liver metastasis (Table 1, “adjuvant treatment 3”).8 To assess the predictive value of the selected markers for this type of adjuvant chemotherapy, clinicopathologic parameters known to be associated with prognosis of advanced CRC patients were also considered in the analysis (Table 1): (1) the gender
Discussion
The aim of the present study was to investigate the predictive value of 8 selected candidate molecular markers for advanced CRC patients treated by resection of liver metastasis and subsequent HAI (FUDR/dexamethasone) and systemic CTP11. Investigated candidate markers were either involved in FUDR/5-FU metabolism (TP, DPD, UP, UK, and TS)16, 17, 18, 19, 20, 21, 22, 23, 29, 30, 31, 32, 33, 34, 35 or associated with cell proliferation and antiapoptosis (Bcl-xl, Survivin, and Cyclin-D1).36, 37, 38,
Surgical therapy for metastatic disease to the liver
Annu Rev Med
(2005)
M. Lise et al.
Colorectal liver metastasis: towards the integration of conventional and molecularly targeted therapeutic approaches
Front Biosci
(2005)
S.S. Yoon et al.
Surgical treatment and other regional treatments for colorectal cancer liver metastases
Oncologist
(1999)
P. Ragnhammar et al.
Swedish Council of technology assessment in health careA systematic overview of chemotherapy effects in colorectal cancer
Acta Oncol
(2001)
N. Kemeny et al.
Phase I/II study of hepatic arterial therapy with floxuridine and dexamethasone in combination with intravenous irinotecan as adjuvant treatment after resection of hepatic metastases from colorectal cancer
J Clin Oncol
(2003)
N. Kemeny et al.
Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer
N Engl J Med
(1999)
G.D. Leonard et al.
Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma
J Clin Oncol
(2005)
N.E. Kemeny et al.
Hepatic arterial infusion after liver resection
N Engl J Med
(2005)
D.J. Sargent et al.
Clinical trial designs for predictive marker validation in cancer treatment trials
J Clin Oncol
(2005)
M.S. Braun et al.
Molecular markers of chemotherapeutic response and toxicity in colorectal cancer
Expert Rev Anticancer Ther
(2007)
D.B. Longley et al.
5-Fluorouracil: mechanisms of action and clinical strategies
Nat Rev Cancer
(2003)
E.A. Kidd et al.
Variance in the expression of 5-fluorouracil pathway genes in colorectal cancer
This result contradicts the findings of prior reports which have demonstrated a significantly worse outcome in CLM patients whose tumours have shown high TS expression.22,32,39 However, several reports have found no association between TS scores and clinical outcome.16,33,40 In the current study, evaluation of the interrelationships among p53, Ki-67 and TS expression showed no associations.
The aim of this study was to assess whether biological markers can provide prognostic information additional to that supplied by the clinical risk score (CRS) in patients with colorectal liver metastases.
A retrospective review of a prospectively maintained database was conducted. Patients selected for this study were treated between 1996 and 2011 with potentially curative liver surgery. Expressions of p53, Ki-67 and thymidylate synthase were assayed using immunohistochemical techniques on tissue microarrays.
A total of 98 (24%) of 406 patients met the inclusion criteria. The median follow-up was 103 months. Analysis revealed a correlation between p53 protein overexpression and high CRS (P = 0.058). Following multivariate analysis, only high CRS remained as an independent negative prognostic predictor of survival (P = 0.018), as well as an indicator of early recurrence of disease (P = 0.010). Of the biological markers investigated, only Ki-67 overexpression was identified as a positive predictor of survival on multivariate analysis (P = 0.038).
Ki-67 overexpression was a positive predictor of survival. Only high CRS remained an independent negative prognostic predictor.
Folate receptor alpha (FRα), encoded by folate receptor 1 (adult) gene, has emerged as a cancer biomarker and potential therapeutic target. In addition, its expression in tumors may offer prognostic information. The aim of this study was to assess the prognostic value of FRα expression and other common molecular markers in resected liver metastases from colorectal cancer. To maximize potential biological differences, we selected two groups of patients with markedly different outcomes as study subjects. Immunohistochemical analysis of FRα expression and other common markers (thymidylate synthase, p53, p27, BCL2, ki67, MLH1, MSH2 and MGMT) on tissue microarrays was carried out on samples from 160 patients; 56 patients survived at least 10 years following liver resection, and 104 died within 2 years of surgery. These markers were evaluated and compared with standard clinical predictors of outcome including a previously validated clinical risk score. Our results showed that in addition to known clinical risk factors, FRα positivity was significantly associated with the early death group (32% compared with 13%; P=0.03). None of the other common molecular markers were differentially expressed between the two groups. On multivariate analysis, clinical risk score, margin status and FRα expression were independently associated with outcome. Specific multivariate comparisons confirmed that FRα expression was associated with outcome independent of the clinical risk score and margin. These data demonstrate that FRα expression is present in a subset of resected hepatic colorectal cancer metastases, and this marker is independently associated with survival after hepatic resection. The prognostic value of FRα expression and the utility of FRα-targeted therapies in stage-IV colorectal cancer patients deserve further exploration.
