BRCA1 and BRCA2: chemosensitivity, treatment outcomes and prognosis

Abstract

BRCA1 and BRCA2 are important breast and ovarian cancer susceptibility genes, and mutations in these two genes confer lifetime risks of breast cancer of up to 80% and ovarian cancer risks of up to 40%. Clinico-pathological studies have identified features that are specific to BRCA1-related breast cancer, but this has been more difficult for BRCA2-related breast cancer. Ovarian cancers due to BRCA1 or BRCA2 mutations cannot usually be distinguished from their non-hereditary counterparts on morphological grounds, but micro-array data suggest that differences do exist. Prognostic studies have shown that breast cancer in a BRCA1 mutation carrier is likely to have a similar, or worse, outcome than that occurring in a BRCA2- or non-carrier of the same age. By contrast, most studies indicate that women developing a BRCA1/2-related ovarian cancer have an improved survival compared with non-carriers, particularly if they receive platinum-based therapy. In support of this, in vitro chemo-sensitivity studies have found that human cells lacking BRCA1 may be particularly sensitive to cisplatinum and to other drugs that cause double-strand breaks in DNA. Nevertheless, in breast cancer, little is known regarding clinically important differences in response to chemotherapy between BRCA1/2 mutation carriers and non-carriers, and between different chemotherapeutic regimens within existing series of BRCA1/2 mutation carriers. There are no published prospective studies. It is hoped that, in the near future, randomised controlled trials will be started with the aim of answering these important clinical questions.