Outcome to Neoadjuvant Cisplatin-Based Chemotherapy in Resectable Muscle-Invasive Bladder Cancer (MIBC) Patients (P) According to Expression Levels of BRCA1, RAP80, and AEG-1

ABSTRACT Background Response to neoadjuvant chemotherapy has been associated with an improvement in survival in MIBC. The analysis of genetic markers involved in DNA repair pathways could be useful to predict chemosensitivity to cisplatin-based regimens. BRCA1 plays a central role in DNA repair and cell-cycle checkpoint control. However, BRCA1 function can be modulated by other DNA repair genes. RAP80 acts upstream of BRCA1 and regulates BRCA1 function after DNA damage. AEG-1 can induce BRCA1 expression and cause chemoresistance by activating PI3K/Akt and NF-KB pathways. Methods Paraffin-embedded pre-treatment tumor samples were collected by transurethral resection from 65 p with resectable MIBC stage T2-4N0M0 treated with neoadjuvant cisplatin-based chemotherapy. Gene expression levels of BRCA1, RAP80 and AEG-1 were quantified by real-time quantitative PCR. Expression levels were divided into terciles and correlated with median survival (MS). Results 33 p were treated with cisplatin, methotrexate and vinblastine (CMV) and 32 p with cisplatin and gemcitabine. Chemotherapy was followed by cystectomy in 60 p. Overall MS was not reached and 5-year survival was 51%. 16 p (38%) with low/intermediate BRCA1 levels had a complete pathological response (pR), while only 1 p (5%) with high BRCA1 levels had a complete pR (P = 0.006). MS was 45 months (m) and 5-year survival was 27% in 21 p with high BRCA1 mRNA levels vs 168 m and 59% in 44 p with low/intermediate levels (P = 0.05). No differences in MS were observed according to RAP80 mRNA levels. MS was 50 m in 15 p with high AEG-1 levels, 45 m in 15 p with intermediate levels, and was not reached in 18 p with low levels, although these differences were not statistically significant (P = 0.3). Conclusions Low/intermediate BRCA1 mRNA expression is associated with better pR and longer MS and 5-year survival to cisplatin-based neoadjuvant chemotherapy in p with MIBC. BRCA1 levels can be useful in customizing chemotherapy in these p. Further studies with larger numbers of p are warranted to elucidate the role of other molecular markers, including AEG-1, in this setting. Disclosure All authors have declared no conflicts of interest.