Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy.
OBJECTIVE
Metastatic renal cell carcinoma (RCC) has a poor prognosis and an unpredictable course. To date, there are no molecular markers which can reliably predict RCC outcome. We investigated whether a novel kidney cancer marker, carbonic anhydrase IX (CAIX), is associated with progression and survival.


METHODS
Immunohistochemical analysis using a CAIX monoclonal antibody was performed on tissue microarrays constructed from paraffin-embedded specimens from patients (N = 321) treated by nephrectomy for clear cell RCC. CAIX staining was correlated with response to treatment, clinical factors, pathologic features, and survival.


RESULTS
CAIX staining was present in 94% of clear cell RCCs. Survival tree analysis determined that a cutoff of 85% CAIX staining provided the most accurate prediction of survival. Low CAIX (</=85%) staining was an independent poor prognostic factor for survival for patients with metastatic RCC, with a hazard ratio of 3.10 (P < 0.001). CAIX significantly substratified patients with metastatic disease when analyzed by T stage, Fuhrman grade, nodal involvement, and performance status (P < 0.001, = 0.001, = 0.009, = 0.005, respectively). For patients with nonmetastatic RCC and at high risk for progression, low CAIX predicted a worse outcome similar to patients with metastatic disease (P = 0.058). Overall expression of CAIX decreased with development of metastasis; as demonstrated by the lower CAIX staining levels in metastatic lesions relative to matched primary tumor specimens (P = 0.036).


CONCLUSIONS
On the basis of our data, CAIX is the most significant molecular marker described in kidney cancer to date. Decreased CAIX levels are independently associated with poor survival in advanced RCC. CAIX reflects significant changes in tumor biology, which should be used to predict clinical outcome and identify high-risk patients in need for adjuvant immunotherapy and CAIX-targeted therapies.
Bui
Matthew H T
MH
Department of Urology, University of California, Los Angeles, California 90095-1738, USA.
Seligson
David
D
Han
Ken-ryu
KR
Pantuck
Allan J
AJ
Dorey
Frederick J
FJ
Huang
Yunda
Y
Horvath
Steve
S
Leibovich
Bradley C
BC
Chopra
Shefali
S
Liao
Shu-Yuan
SY
Stanbridge
Eric
E
Lerman
Michael I
MI
Palotie
Aarno
A
Figlin
Robert A
RA
Belldegrun
Arie S
AS
D018262:Adenocarcinoma, Clear Cell / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000032:analysis / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000032:analysis / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis / Q000378:metabolism*; D009367:Neoplasm Staging; D009392:Nephrectomy; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis; D013997:Time Factors
D000951:Antigens, Neoplasm; D009363:Neoplasm Proteins; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases