Experimentally derived metastasis gene expression profile predicts recurrence and death in patients with colon cancer.
OBJECTIVE
Staging inadequately predicts metastatic risk in patients with colon cancer. We used a gene expression profile derived from invasive, murine colon cancer cells that were highly metastatic in an immunocompetent mouse model to identify patients with colon cancer at risk of recurrence.


METHODS
This phase 1, exploratory biomarker study used 55 patients with colorectal cancer from Vanderbilt Medical Center (VMC) as the training dataset and 177 patients from the Moffitt Cancer Center as the independent dataset. The metastasis-associated gene expression profile developed from the mouse model was refined with comparative functional genomics in the VMC gene expression profiles to identify a 34-gene classifier associated with high risk of metastasis and death from colon cancer. A metastasis score derived from the biologically based classifier was tested in the Moffitt dataset.


RESULTS
A high score was significantly associated with increased risk of metastasis and death from colon cancer across all pathologic stages and specifically in stage II and stage III patients. The metastasis score was shown to independently predict risk of cancer recurrence and death in univariate and multivariate models. For example, among stage III patients, a high score translated to increased relative risk of cancer recurrence (hazard ratio, 4.7; 95% confidence interval, 1.566-14.05). Furthermore, the metastasis score identified patients with stage III disease whose 5-year recurrence-free survival was >88% and for whom adjuvant chemotherapy did not increase survival time.


CONCLUSIONS
A gene expression profile identified from an experimental model of colon cancer metastasis predicted cancer recurrence and death, independently of conventional measures, in patients with colon cancer.
Smith
J Joshua
JJ
Department of Surgery, Vanderbilt Medical Center, Nashville, TN, USA.
Deane
Natasha G
NG
Wu
Fei
F
Merchant
Nipun B
NB
Zhang
Bing
B
Jiang
Aixiang
A
Lu
Pengcheng
P
Johnson
J Chad
JC
Schmidt
Carl
C
Bailey
Christina E
CE
Eschrich
Steven
S
Kis
Christian
C
Levy
Shawn
S
Washington
M Kay
MK
Heslin
Martin J
MJ
Coffey
Robert J
RJ
Yeatman
Timothy J
TJ
Shyr
Yu
Y
Beauchamp
R Daniel
RD
D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000556:secondary / Q000628:therapy; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D018579:Patient Selection; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D019564:Unnecessary Procedures