A Step Towards Chemoprevention: Biomarkers for BRCA1 Loss of Heterozygosity

Abstract

Breast cancer is the leading cause of cancer related deaths in women. Every year more than 2 million women in the world are diagnosed with breast cancer, and almost a third lose their lives to this disease. Although all women can suffer from breast cancer, some of them have hereditary mutations that increase their risk. One of the commonly affected hereditary genes is breast cancer gene 1 (BRCA1), where one of the two gene copies is defective. BRCA1 is a protein involved in the repair of double strand breaks in the DNA and is essential for genome integrity. The loss of the remaining healthy copy, termed loss of heterozygosity (LOH), is a cancer initiating event. The risk of developing breast cancer in women carrying BRCA1 mutations is increased by 50-85% compared to the rest of the female population. These women more often suffer from triple negative breast cancer which tends to occur earlier in life, is more aggressive and associated with tumor reoccurrence. Given the high cancer risk and the negative prognosis for BRCA1 mutation carriers, many undergo preventive surgery. The surgical removal of the breasts and the ovaries can reduce the risk of breast cancer almost to zero. However, these surgeries bear a strong physical and psychological burden on the patients, who later struggle with body image, sexuality and have a decreased or even loss of fertility. For this reason, many women still opt to delay these surgeries and resort to routine examinations and mammographs. These surveillance approaches support early detection, but do not prevent cancer incidence. Therefore, recent efforts have shifted towards chemoprevention, the preventive administration of drugs with proven efficacy against breast cancer. Some clinical trials have tested anti-hormone agents such as tamoxifen. These are effective treatments against hormone-positive cancers that rely on estrogen signaling for tumor growth. However, triple negative breast cancers, the most common subtype in BRCA1 mutation carriers, lack these hormone receptors and might therefore not benefit from these anti-estrogen drugs. Another proposed approach is the use of PARP inhibitors. These drugs block the alternative DNA repair pathways that are active upon BRCA1 loss to induce deathly DNA damage and selectively kill BRCA1-mutated cells. Only, currently there are no clinical trials using PARP inhibitors in a preventive setting. Overall, chemoprevention is a promising approach, however it requires detection of the BRCA1 deficient mammary epithelial cells to determine which patients may benefit from it and test its efficacy. Unfortunately, as of now there is no biomarker for LOH of BRCA1 that selectively marks these BRCA1-deficient cells. To find such biomarker we need to understand the function of BRCA1 and investigate whether there are factors that get upregulated upon BRCA1 loss. In this review we examine candidate biomarkers that arise either through the enzymatic activity of BRCA1, through its role in transcriptional regulation or compensatory DNA repair proteins that are upregulated in the absence of BRCA1. Additionally, we examine past and ongoing clinical trials and discuss how a biomarker of BRCA1 LOH might be integrated to improve patient care.