Prognostic significance of BRCA1 expression defined in glioblastoma multiforme
The prognostic significance of BRCA1 protein expression in glioblastoma multiforme (GBM) tumors has been determined for the first time. An investigation carried out by the Radiation Therapy Oncology Group assessed four distinct molecular biomarkers in GBM, the results of which suggested that BRCA1 was the sole marker to correlate with overall survival. The findings were reported at the recent Annual Meeting of the American Society for Radiation Oncology (18–21 October 2015, TX, USA).
Patients with GBM tumors expressing low levels of BRCA1 were demonstrated to be associated with prolonged survival when compared with GBM patients with tumors expressing higher levels of the proteins – median overall survival was found to be 18.9 vs 4.8 months, respectively.
Archived tissue microarrays of tumor samples isolated from 66 GBM patients who had participated in Radiation Therapy Oncology Group clinical trials underwent analysis for RAD51, BRCA1, PTEN, and miRNA-210 protein expression. These 66 patients had all been treated with surgery, radiotherapy and non-temozolomide chemotherapy, and had a similar overall survival.
“BRCA1 is a tumor suppressor gene that is involved in DNA repair. Mutations of this gene, or deficient protein due to epigenetic changes, lead to DNA damage repair failure,” explained the study’s principal investigator Maria Vasilakopoulou (Pitié-Salpêtrière Hospital, Paris, France). “The study results suggest strongly that low BRCA1 protein expression in the GBM tumor, and the consequent low DNA repair, causes the cancer cells to be more susceptible to DNA-damaging cancer treatment.”
Patients newly diagnosed with GBM have a poor prognosis, with an average median survival of 14–16 months. Vasilakopoulou reported how these findings could have implications outside of prognosis: “Moreover, as BRCA1 seems to be a predictive biomarker of unfavorable survival in GBM, patients identified as high expressers could be treated with agents that downregulate BRCA1 thus sensitizing them to other cytotoxic therapies.”
She continued: “Targeting BRCA1 is a promising therapeutic strategy and several agents such as PARP-inhibitors may target BRCA1 leading to failure of DNA damage repair and apoptosis preferentially in BRCA1-defective cells.”
Further investigation into these findings is required both in vitro and in the clinic in order to evaluate the correlation between BRCA1 expression and response to these targeted therapies. As Vasilakopoulou highlighted, the US FDA’s recent approval of a PARP inhibitor for BRCA-mutated ovarian cancer, combined with continuing research for this new class of targeted therapy, could culminate in this therapeutic strategy becoming an option that may benefit some GBM patients.
“These results suggest that BRCA1 testing could play a future role in the development of more individualized treatment options for patients whose tumor genetic profile shows low BRCA1 protein expression,” commented senior abstract author Jonathan Knisely of the North Shore-LIJ Cancer Institute (NY, USA).
As a first step, the team are now planning to validate these results in another cohort of GBM patients.
