A prognostic classifier for patients with colorectal cancer liver metastasis, based on AURKA, PTGS2 and MMP9.
BACKGROUND
Prognosis of patients with colorectal cancer liver metastasis (CRCLM) is estimated based on clinicopathological models. Stratifying patients based on tumor biology may have additional value.


METHODS
Tissue micro-arrays (TMAs), containing resected CRCLM and corresponding primary tumors from a multi-institutional cohort of 507 patients, were immunohistochemically stained for 18 candidate biomarkers. Cross-validated hazard rate ratios (HRRs) for overall survival (OS) and the proportion of HRRs with opposite effect (P(HRR < 1) or P(HRR > 1)) were calculated. A classifier was constructed by classification and regression tree (CART) analysis and its prognostic value determined by permutation analysis. Correlations between protein expression in primary tumor-CRCLM pairs were calculated.


RESULTS
Based on their putative prognostic value, EGFR (P(HRR < 1) = .02), AURKA (P(HRR < 1) = .02), VEGFA (P(HRR < 1) = .02), PTGS2 (P(HRR < 1) = .01), SLC2A1 (P(HRR > 1) < 01), HIF1α (P(HRR > 1) = .06), KCNQ1 (P(HRR > 1) = .09), CEA (P (HRR > 1) = .05) and MMP9 (P(HRR < 1) = .07) were included in the CART analysis (n = 201). The resulting classifier was based on AURKA, PTGS2 and MMP9 expression and was associated with OS (HRR 2.79, p < .001), also after multivariate analysis (HRR 3.57, p < .001). The prognostic value of the biomarker-based classifier was superior to the clinicopathological model (p = .001). Prognostic value was highest for colon cancer patients (HRR 5.71, p < .001) and patients not treated with systemic therapy (HRR 3.48, p < .01). Classification based on protein expression in primary tumors could be based on AURKA expression only (HRR 2.59, p = .04).


CONCLUSIONS
A classifier was generated for patients with CRCLM with improved prognostic value compared to the standard clinicopathological prognostic parameters, which may aid selection of patients who may benefit from adjuvant systemic therapy.
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Jeroen A C M
JA
Goos
Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
Veerle M H
VM
Coupé
Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
Mark A
MA
van de Wiel
Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Begoña
B
Diosdado
Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Pien M
PM
Delis-Van Diemen
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Annemieke C
AC
Hiemstra
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Erienne M V
EM
de Cuba
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Jeroen A M
JA
Beliën
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
C Willemien
CW
Menke-van der Houven van Oordt
Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
Albert A
AA
Geldof
Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Gerrit A
GA
Meijer
Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
Otto S
OS
Hoekstra
Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Remond J A
RJ
Fijneman
D064096:Aurora Kinase A / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000145:classification / Q000378:metabolism / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000145:classification / Q000378:metabolism / Q000556:secondary*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate
D014408:Biomarkers, Tumor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C576917:AURKA protein, human; D064096:Aurora Kinase A; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
biomarker; classifier; colorectal cancer; liver metastasis; prognosis