Association of Ki-67, p53, and bcl-2 expression of the primary non-small-cell lung cancer lesion with brain metastatic lesion.
OBJECTIVE
The study was conducted to determine whether immunohistochemical analysis of Ki-67, p53, and bcl-2 in patients with non-small-cell lung cancer is associated with a higher rate of brain metastases and whether the intrapatient expression of these biomarkers (in the primary tumors vs. brain lesions) is similar.


METHODS
At the M. D. Anderson Cancer Center, tumors from 29 case patients with primary lung tumor and brain metastasis and 29 control patients with primary lung tumor but no brain metastasis were resected and examined for immunohistochemical expression. Ki-67, p53, and bcl-2 were analyzed in resected primary lung, lymph node, and metastatic brain tumors. Each control patient was matched by age, gender, and histology to a patient with brain metastasis.


RESULTS
No significant differences in patient survival characteristics were detected between the case group and control group. Also, difference in patient outcome between the two groups was not generally predicted by biomarker analysis. However, when the groups were combined, the biomarker analysis was predictive for certain patient outcome end points. Using median values as cutoff points between low and high expression of biomarkers, it was observed that high expression of Ki-67 (>40%) in lung primaries was associated with poorer disease-free survival (p = 0.04), whereas low expression of p53 in lung primaries was associated with poorer overall survival (p = 0.04), and these patients had a higher rate of nonbrain distant metastases (p = 0.02). The patients with brain metastases were particularly prone to developing nonbrain distant metastases if the percentage of p53-positive cells in brain metastases was low (p = 0.01). There was a positive correlation in the expression of Ki-67 (p = 0.02)(r(2) = 0.1608), as well as p53 (p < 0.001) (r(2) = 0.7380), between lung primaries and brain metastases. Compared to Ki-67 and p53, bcl-2 was the least predictive.


CONCLUSIONS
Differences in biomarker expression between the case and control groups did not serve as significant predictors of brain metastasis or patient survival. There was a strong correlation between lung primary biomarker expression and brain metastasis expression for Ki-67 and p53. Univariate analysis showed that low p53 and high Ki-67 expression predicted poor prognosis. This study shows that there may be a strong correlation between biomarker expression in non-small-cell lung cancer primary tumors and their brain metastases.
Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Robbin S
RS
Bubb
Ritsuko
R
Komaki
Tsutomu
T
Hachiya
Ivan
I
Milas
Jae Y
JY
Ro
Lauren
L
Langford
Raymond
R
Sawaya
Joe B
JB
Putnam
Pamela
P
Allen
James D
JD
Cox
Timothy J
TJ
McDonnell
William
W
Brock
Waun K
WK
Hong
Jack A
JA
Roth
Luka
L
Milas
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis*; D008175:Lung Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53