Expression of the epidermal growth factor receptor and Her-2 are predictors of favorable outcome and reduced complete response rates, respectively, in patients with muscle-invading bladder cancers treated by concurrent radiation and cisplatin-based chemotherapy: a report from the Radiation Therapy Oncology Group.
OBJECTIVE
Erb-1 (epidermal growth factor receptor, EGFR) and Erb-2 (Her-2) are two of the best characterized members in the EGFR pathway. In many tumor types, overexpression of these proteins is associated with enhanced malignant potential. Our objective in this study was to investigate the clinical relevance of EGFR and Her-2 expression in bladder cancer cases from four prospective Radiation Therapy Oncology Group (RTOG) bladder preservation trials using cisplatin-containing chemoradiation (RTOG 8802, 8903, 9506, and 9706).


METHODS
Tumors from 73 cases from patients with muscle-invading T2-T4a bladder cancers had slides interpretable for EGFR staining; 55 cases had slides interpretable for Her-2 staining. Additionally, the respective prognostic values of p53, pRB, and p16 immunostaining were concomitantly examined. Staining and interpretation of staining were done in a blinded manner, without knowledge of clinical outcome. Staining was judged as positive or negative. Subsequently, staining was correlated with clinical outcome.


RESULTS
On univariate analysis, EGFR positivity was significantly associated with improved overall survival (p = 0.044); disease-specific survival (DSS) (p = 0.042); and DSS with intact bladder (p = 0.021). There was also a trend for association between EGFR expression and reduced frequency of distant metastasis (p = 0.06). On multivariate analysis adding tumor stage, tumor grade, whether a visibly complete transurethral resection of bladder tumor (TURBT) was done or not, and patient age to the model, EGFR positivity was significantly associated with improved DSS. On univariate analysis, Her-2 positivity was significantly associated with reduced complete response (CR) rates (50% vs. 81%, p = 0.026) after chemoradiation which remained significant on multivariate analysis. The other markers examined in this study were not found to have any prognostic value in this setting.


CONCLUSIONS
Epidermal growth factor receptor expression appears to correlate significantly with improved outcome in bladder cancer, whereas Her-2 expression is significantly associated only with reduced CR rates after chemoradiation. Further investigations are warranted into how EGFR family members regulate response to chemoradiation in bladder cancer and their potential therapeutic implications.
Chakravarti
Arnab
A
Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. achakravarti@partners.org
Winter
Kathryn
K
Wu
Chin-Lee
CL
Kaufman
Donald
D
Hammond
Elizabeth
E
Parliament
Matthew
M
Tester
William
W
Hagan
Michael
M
Grignon
David
D
Heney
Niall
N
Pollack
Alan
A
Sandler
Howard
H
Shipley
William
W
D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use; D003131:Combined Modality Therapy; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy
D000970:Antineoplastic Agents; D002945:Cisplatin; D019941:Cyclin-Dependent Kinase Inhibitor p16; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53