BRCA1/2 genetic background-based therapeutic tailoring of human ovarian cancer: hope or reality?
Pierosandro Tagliaferri, Monica Ventura, Francesco Baudi,
Iole Cucinotto, Mariamena Arbitrio, Maria Teresa Di Martino, and
Pierfrancesco Tassone.
Published October 13, 2009 in the Journal of Ovarian Research (2:14).
Background
BRCA1 and BRCA2 are onco-suppressor genes that are involved in DNA repair, cell cycle regulation, apoptosis, and genome integrity control. Mutations of these genes have been shown to be related to hereditary breast and ovarian cancer, as well as prostate, colon, pancreatic, and male breast cancer. It has been estimated that at least 15% of ovarian cancer cases are inherited due to mendellian autosomic dominant inheritance of cancer predisposing mutations, of which 90% are mutations of BRCA1/2 and 10% are mutations of MLH1/2. This paper discusses the possibility of altering treatment decisions based on determining if cancer predisposing mutations are the cause of tumor formation.
BRCA1 and BRCA2 gene function and role in the DNA repair
Without functional BRCA1/2 genes, tumor cells are very unstable. BRCA1 and BARD1 form a hetero-dimeric complex that functions in DNA repair, and cells with these defective genes have been shown to be sensitive to DNA damaging agents and defects in DNA Double-stranded break (DSB) repair by homologous recombination (HR). BRCA1 is part of a large multi-protein complex (called BASC), that recognizes DNA damage and controls cell cycle checkpoints. It stops the transmission of genetic damage by only allowing the cell to progress once DNA repair has occurred. BRCA2 directly influences DNA repair by driving RAD51 (another gene involved in HR) to the DSB site. It has been shown that cells without BRCA1/2 cannot repair DSB by HR. This leads to repair using error prone DNA repair pathways (like NHEI and SSA).
Chemosensitivity of BRCA1/2 -related ovarian tumors
Evidence has shown that tumor cells without BRCA1/2 are highly sensitive to platinum derivatives used in chemotherapy drugs, because of their defect in DNA repair. Researchers have found a direct correlation between BRCA1 mRNA expression levels and chemo patient survival. Patients with low- intermediate levels of BRCA1 mRNA expression had a better outcome (57month survival) compared to patients with high BRCA1 mRNA expression levels (18.2months, p=0.0017). An important study was conducted on Jewish women tested for hereditary ovarian cancer and compared mutation positive and mutation negative survival rates. Survival was better by 5 years in individuals identified as mutation positive. Such studies may be proof that ovarian cancer in BRCA1/2 mutation carriers is a different disease, and the choice of treatment has important implications.
BRCA-ness in the current and evolving scenario of management of ovarian cancer
Currently, there has been evidence for a “BRCA-ness” syndrome in which BRCA1/2 mutation carriers have characteristic serous histology, high response to platinum-based treatment, longer treatment free intervals (TIFs) between relapses, and improved overall survival.
This scenario is evolving as PARP inhibitors are being shown to be a new effective treatment against BRCA1/2 related tumors. PARP (poly ADP Ribose Polymerase) proteins are involved in regulation of transcription and cell death, and are important in events leading up to the formation of cancer or inflammatory disease. Thus, PARP inhibitors used as a chemotherapy drug are effective in treatment of tumors with functional defects in DNA repair mechanisms, such as BRCA1/2 related tumors (Figure1). Breaks in the tumor cells DNA caused by chemotherapy drugs are often repaired by PARP, thus, when inhibited, this blocks DNA repair by PARP and tumor cells cannot grow.
Conclusion
Findings have allowed a more effective treatment approach for BRCA1/2 related ovarian tumors using both current drugs, like platinum derivatives, and new drugs, like PARP inhibitors. There may be a potential to develop molecular marker-based treatment to identify BRCA mRNA expression levels in patients and improve their prognosis. Using genetic background to identify the best treatment for the individual is an emerging and promising development in ovarian cancer patients.
My Opinion
Overall, this paper was informative and generally easy to read. It was a bit hard to understand for someone with little background information on cancer and cancer treatments and required some investigation on my part to understand certain terms. This could be improved by explaining concepts more in detail and providing more definitions. Also, I think the paper could be improved by using more figures in explaining topics, such as how PARP works in normal cells and how PARP inhibitors can be effective in BRCA1/2 mutant cells. I find the figure they provided, shown above, to be a bit confusing and overwhelming, and may be better improved if broken up into several figures. Otherwise, I found this paper to be very interesting. I was especially interested in the idea that not all ovarian cancer patients are the same and that tumors may form for very different reasons. Thus, viewing patients on an individual bases rather than viewing all patients the same, can help to improve the treatment and survival of patients with ovarian cancer.
