High frequency of MAGE‐A4 and MAGE‐A9 expression in high‐risk bladder cancer

Abstract Cancer‐testis (CT) genes encode proteins that are ideal targets for cancer immunotherapy because of their restricted expression in normal tissues and frequent expression in cancers. We previously observed that MAGE‐A9 was one of the CT genes most frequently expressed in bladder tumors. To confirm that observation and evaluate the potential prognostic value of MAGE‐A9 protein, we analyzed its expression by immunohistochemistry in 493 primary bladder tumors and 33 lymph node metastases, in comparison with MAGE‐A4 protein, also frequently expressed in bladder tumors. Overall, MAGE‐A4 and MAGE‐A9 were observed, respectively, in 38% and 63% of nonmuscle‐invasive tumors, 48% and 57% of muscle‐invasive tumors, 65% and 84% of carcinomas in situ and in 73% and 85% of lymph node metastases. Expression was associated with higher grade (MAGE‐A4, p = 0.007; MAGE‐A9, p = 0.012). In multivariate Cox regression analyses, expression of MAGE‐A9 in pTa tumors was associated with recurrence (HR = 1.829; p = 0.010). In univariate analyses, MAGE‐A4 expression in these same tumors was associated with progression to muscle‐invasive cancer (HR = 7.417, p = 0.013). MAGE‐A9 expression was even more predictive of progression as all tumors that progressed expressed this antigen. In muscle‐invasive bladder tumors, no association was found between expression of either MAGE and bladder cancer‐specific death. In conclusion, MAGE‐A9 is a target of choice for bladder cancer immunotherapy as it is expressed in 60% of bladder tumors, predominantly high‐grade tumors, and at higher frequency in pTis and metastatic tumors. Moreover, in pTa tumors, an immunotherapy targeting MAGE‐A9 could be protective against recurrence and progression to more advanced cancer. © 2009 UICC