Expression of p16 in lymph node metastases of adjuvantly treated stage III colorectal cancer patients identifies poor prognostic subgroups: a retrospective analysis of biomarkers in matched primary tumor and lymph node metastases.
BACKGROUND
The objective of identifying protein biomarkers for patients with stage III and IV colorectal cancer is to improve risk stratification and, thus, to identify patients in the postoperative setting who may benefit from more targeted treatment. The objective of the current study was to determine the prognostic value of 19 protein markers assessed in primary tumors and matched lymph node (LN) metastases from patients with stage III and IV colorectal cancer.


METHODS
Matched primary tumors and LN metastases from 82 patients with stage III and IV colorectal cancer were mounted onto a multiple-punch tissue microarray and were stained for 19 protein markers involved in tumor progression (β-catenin, E-cadherin, epidermal growth factor receptor, phosphorylated extracellular signal-regulated kinase [pERK], receptor for hyaluronic acid-mediated motility, phosphorylated protein kinase B, p21, p16, B-cell lymphoma 2, Ki67, apoptotic protease activating factor 1, mammalian sterile 20-like kinase 1, Raf kinase inhibitor protein, vascular endothelial growth factor, ephrin type-B receptor 2, matrix metalloproteinase 7, laminin5γ2, mucin 1 [MUC1], and caudal-related homeobox 2). The prognostic effects of biomarkers in both primary tumor and positive LNs were assessed.


RESULTS
MUC1, pERK and p16 in LN (P=.002, P=.014, and P=.002, respectively) had independent prognostic value. In patients with stage III disease who received adjuvant treatment, negative p16 expression was associated with highly unfavorable outcomes overall (hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.1-0.6; P=.005) when the analysis was stratified by pathologic tumor classification (HR, 0.25; 95% CI, 0.1-0.7; P=.005), age (HR, 0.23; 95% CI, 0.1-0.6; P=.004), and LN ratio (HR, 0.26; 95% CI, 0.1-0.7; P=.007); and, in multivariate analysis, it was associated with performance status and the receipt of folic acid treatment (HR, 0.29; 95% CI, 0.09-0.89; P=.03).


CONCLUSIONS
The loss of p16 in LN metastases contributed to adverse outcomes in adjuvantly treated patients with stage III colorectal cancer independent of pathologic tumor classification, age, LN ratio, performance status, or folic acid treatment. The current results support the investigation of p16 as a prognostic and potential predictive biomarker for future randomized trials of patients with stage III colorectal cancer.
Karamitopoulou
Eva
E
Second Department of Pathology, University of Athens, Attikon University Hospital, Athens, Greece.
Zlobec
Inti
I
Koumarianou
Anna
A
Patsouris
Efstratios S
ES
Peros
George
G
Lugli
Alessandro
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis / Q000175:diagnosis* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis
D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16