BRCA1 mRNA expression and outcome to neoadjuvant cisplatin-based chemotherapy in bladder cancer

Abstract

Background: Neoadjuvant chemotherapy has shown a modest benefit in muscle-invasive bladder cancer patients; however, the subset of patients most likely to benefit has not been identified. BRCA1 plays a central role in DNA repair pathways and low BRCA1 expression has been associated with sensitivity to cisplatin and longer survival in lung and ovarian cancer patients. Patients and methods:We assessed BRCA1 messenger RNA expression levels in paraffin-embedded pre-treatment tumor samples obtained by transurethral resection from 57 patients with locally advanced bladder cancer subsequently treated with neoadjuvant cisplatin-based chemotherapy. BRCA1 levels were divided into terciles and correlated with pathological response and survival.Results: A significant pathological response (pT0-1) was attained in 66% (24 of 39) of patients with low/intermediate BRCA1 levels compared with 22% (4 of 18) of patients with high BRCA1 levels (P = 0.01). Median survival was 168 months in patients with low/intermediate levels and 34 months in patients with high BRCA1 levels (P = 0.002). In the multivariate analysis for survival, only BRCA1 expression levels and lymphovascular invasion emerged as independent prognostic factors.Conclusions: Our data suggest that BRCA1 expression may predict the efficacy of cisplatin-based neoadjuvant chemotherapy and may help to customize therapy in bladder cancer patients.

Co-expression of ERCC1 and Snail is a prognostic but not predictive factor of cisplatin-based neoadjuvant chemotherapy for bladder cancer

“…Takata et al reported that 14 genes were found to be predictive of pCR and may be prognostic factors in patients with bladder cancer treated with neoadjuvant M-VAC therapy (10,26). With regard to DNA repair genes, BRCA1 mRNA was reported to predict the efficacy of cisplatin-based NC (8). In the present study, although the co-expression of Snail and ERCC1 was not a significant factor for the prediction of CR to NC, notably, the co-expression of the proteins, and not just the individual expression of ERCC1 or Snail, was identified as significant prognostic factors for shorter DFS and OS in the patients treated with a cisplatin-based regimen and also those treated with the M-VAC regimen.…”

“…Neoadjuvant chemotherapy (NC) with cisplatin-based combination chemotherapy significantly improved the 5-year survival rate in two meta-analysis studies (4,5) and pathological complete response (pCR) with NC was correlated with survival (6,7). Although a number of studies have discussed factors which predict pCR or a favorable survival rate (8)(9)(10), none of the factors has been proven in a clinical study.…”

A DNA Repair Protein BRCA1 as a Potentially Molecular Target for the Anticancer Platinum Drug Cisplatin

“…Recently, a number of clinical studies have examined the utilization of this BRCA1 dysfunction in response to the DNA-damaging drug cisplatin. A pathological complete response (pCR) with excellent compliance was observed in cancer patients with BRCA1 mutations (Byrski et al, 2009;Font et al, 2010;Quinn et al, 2007;Silver et al, 2010;Taron et al, 2004). This indicates that patients with BRCA1 dysfunction gain more benefit from treatments that exert their effects by causing DNA damage.…”

Aktuelle Entwicklungen in der Diagnostik und Therapie des Harnblasenkarzinoms

“…Ein weiterer prognostischer Marker ist das BRCA1 ("breast cancer 1"), welches ebenfalls eine Rolle für die Reparatur von DNA-Schäden durch Cisplatin spielt. Bei Patienten, die mit eine neoadjuvanten Chemotherapie behandelt worden sind, zeigt sich ebenfalls ein statistisch signifikanter Überlebensvorteil, wenn eine niedrige BRCA1-Expression vorliegt [20]. Die mRNA-Expression von Survivin und Emmprin konnte in einer Microarray-basierten Analyse ebenfalls als unabhängige Prognosemarker für das Überleben von Patienten nach Cisplatin-basierter Chemotherapie identifiziert werden [21].…”