Mutations in the BRCA1 and BRCA2 genes, which are inherited by 1 in 400 and 1 in 800 people respectively, significantly increase the risk of certain cancers such as ovarian, breast, pancreatic and prostate cancer.
In 2016, a new class of drugs, PARP inhibitors, was found to be very effective against tumors linked to the BRCA mutation. However, nearly half of women with ovarian cancer experience a recurrence of the disease within five years.
An international team led by the University of Geneva (UNIGE) in Switzerland, the University Hospitals of Geneva (HUG), the Center Léon Bérard in Lyon, France, the Institut Curie, the French collaborative group ARCAGY-GINECO and the European consortium ENGOT, examined the genetic data of 233 patients included in the phase III pre-marketing clinical trial of olaparib. Olaparib is a PARP inhibitor added to bevacizumab, a drug already used to treat ovarian cancer.
The researchers found that the success of PARP inhibitors depends on the precise location of the mutation on the gene. These results, to be read in the journal Annals of Oncology, show that very high precision medicine is possible in oncology.
mutation
The BRCA1 and BRCA2 genes code for proteins involved in the repair of DNA double-strand breaks, a particularly severe form of DNA damage, and thus play an essential role in maintaining the genomic stability of cells. When they are mutated, the cells are less able to repair damaged DNA, a phenomenon that favors the development of cancers.
“The resulting cancers are particularly aggressive,” said Intidhar Labidi-Galy, researcher in the Department of Medicine and the Center for Translational Research in Onco-Haematology of the UNIGE Faculty of Medicine, tenured physician in the Department of oncology from the University Hospitals of Geneva, and corresponding author of the study.
“Ovarian cancer, often with a very poor prognosis, is one of the most frequent cancers in women carrying a mutation in one of these two genes.
The recent introduction of PARP protein inhibitors – including olaparib – is a major therapeutic advance. For the first time, a treatment with a significant gain in overall survival has been proposed.
“But although previous studies have shown PARP inhibitors to be highly effective in BRCA1 and BRCA2-associated cancers, nearly half of patients saw their cancer recur. Why did this happen? That’s what we wanted to decipher here,” Labidi-Galy said.
Drugs of unequal effectiveness
The research team conducted an analysis of BRCA1 and BRCA2 mutations in 233 patients enrolled in the Phase III clinical trial PAOLA-1, a pre-marketing study of olaparib given in combination with the anti-angiogenic drug bevacizumab , already used to treat ovarian cancer. The patients suffered from advanced ovarian cancer and all carried a mutation of the BRCA1 gene (159 patients) or the BRCA2 gene (74 patients).
“We decided to increase the precision of our analyzes by detailing the mutations involved, and especially what differentiated those sensitive to the drug from those who were less so”, explains Isabelle Ray-Coquard, professor of cancerology at the Léon Bérard Center. . affiliated with the National Federation of Cancer Centers (CLCC) – the Unicancer network, and the Claude Bernard University of Lyon, which supervised this work.
“And the difference comes from the location of the mutation on the gene: if the mutation is located in the DNA-binding domain, the drug is actually much more effective.”
DNA-binding domains are protein motifs capable of binding DNA and involved in the regulation of gene expression.
“PARP inhibitors aim to create an accumulation of DNA breaks in mutated cells, leading to their rapid death before they can create malignant tumors,” said Manuel Rodrigues, a hospital doctor at Institut Curie. and co-first author of the article.
“It would seem that mutations in a DNA-binding domain accelerate this process and significantly increase the effectiveness of the drug. This is less the case when the mutation concerns other functional parts of the gene.
International university study
These results highlight the need for very high precision medicine in oncology.
”It is undeniable that this class of drugs is extremely effective in a large proportion of patients – some even seem completely cured, whereas a few years ago they would have been doomed, and 90% of people carrying a mutation in a DNA-binding domain of the BRCA1 gene did not relapse at the time of analysis. But it is important to understand the precise mechanism of action of the drugs and to refine the treatments according to the genetic profile of the patients and their tumors. Here, the location of the mutation is the key point,” Ray-Coquard said.
This international academic study is the first of its kind and is part of a precision oncology approach, in which the decoding of the genome of patients and tumors is essential. The latter makes it possible to better target diseased cells by developing specific inhibitors, which will also make it possible to limit side effects.
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