Like all genetic material, the BRCA-1 and BRCA-2 gene can undergo a series of mutations or alterations, in such a way that its structure changes and becomes inactive. When this occurs, they no longer code for the synthesis of the protein responsible for DNA repair.
As a result, cells are more likely to have additional genetic alterations that can result in cancer. Specifically, mutations in these genes increase the risk of breast and ovarian cancer.
Triple negative breast cancer is a type of breast neoplasm that does not have any of the receptors usually found in this disease. Therefore, neither progesterone receptors, nor estrogen receptors, nor HER-2 are overexpressed. This type of cancer is today one of those with the worst prognosis, since the therapeutic arsenal is mainly reduced to chemotherapy.
Triple negative breast cancer represents approximately 12-17% of all breast cancer cases. It is characterized by a high proliferation rate and a high capacity to generate metastasis. It is for this reason, and the difficulty in treating it, that it has a worse prognosis.
One of the most frequent molecular events in these tumors is the alteration of the function of the BRCA protein. Among breast cancer patients with hereditary BRCA-1 mutation, more than 80% have triple-negative breast cancer. Furthermore, it is estimated that around 15% of patients with ovarian cancer and 5% of patients suffering from breast, pancreatic or prostate cancer have inherited mutations in the BRCA-1 or BRCA-2 gene.
Treatment of triple negative cancer with mutation in the BRCA-1 and BRCA-2 genes
In December 2014, applications for marketing authorization for olaparib as monotherapy were approved for the treatment of advanced ovarian cancer with a mutation in these genes. Based on these results, the effectiveness of this drug for the treatment of advanced breast cancer was analyzed in previously treated patients who had mutations in the BRCA-1 and BRCA-2 gene.
When applying the maximum tolerated dose of olaparib, which is 400 milligrams every 12 hours in capsules, an objective response rate was observed in patients with triple-negative breast cancer that was 54%. This means that 7 out of 13 patients had a good reaction.
Other alterations that affect the BRCA protein
In addition to the mutations of the genes mentioned, there are other alterations that may be responsible for the abnormal function of the BRCA protein. One of them is the methylation of these genes, which means that a methyl chemical group (CH3-) is added to the promoter of these genes.
The promoter of a gene is the region of DNA that controls the initiation of transcription of a certain portion. In clearer terms, it is the part of DNA that orders the production of a type of protein through RNA.
Therefore, since these genes are methylated, they cannot synthesize the protein responsible for suppressing tumor growth. BRCA-1 and BRCA-2 gene promoter methylation has been seen in several neoplasms:
- 5-20% in ovarian cancer
- 50% in gastric cancer
- 29-59% in breast cancer
Conclusion
The BRCA-1 and BRCA-2 genes play an important role in breast oncology. A high percentage of breast cancer patients who have alterations in these genes, whether mutations or methylations, suffer from the triple negative form. Their prognoses are worse and available treatments are still limited.
It is essential to continue researching in this area to be able to develop new therapeutic options and continue advancing in the fight against this disease. The genetic aspect of breast cancer is an area still with much hope ahead.
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