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.

Premature senescence is a major response to DNA cross-linking agents in BRCA1-defective cells: implication for tailored treatments of BRCA1 mutation carriers

“…The hypersensitivity to ICL inducers observed in our cell models is consistent to what previously reported for the HCC1937 cell line (in which this phenotype was reversed by ectopic restoration of BRCA1 expression) and is in line with the observation that BRCA1 defects represent favorable prognostic factors for ovarian cancer patients treated with platinum compounds (34)(35)(36).…”

Applications of Fluorescence for Detecting Rare Sequence Rearrangements In Vivo

“…36 In contrast, cancer cells deficient in HR (e.g., breast tumors with BRCA2 mutations 37,38 ) are rendered sensitive to chemotherapeutic agents that induce replication fork breakdown. [39][40][41][42] Therefore, knowledge about HR capacity is relevant both to one's risk of developing cancer 13,14,19 and to the response of a tumor to chemotherapy. [39][40][41][42][43] Although HR is an important pathway for overcoming the potential lethality and mutagenicity of replicative stress, studying HR has been difficult since many key HR proteins are either essential for viability [44][45][46][47][48][49] or possibly sufficiently redundant that their absence does not fully reveal the role of this pathway in vivo.…”

Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells

“…A subsequent systematic review by (Stordal et al 2009), revealed that BRCA1 was the mostly likely genetic player in this relationship. Cells with BRCA1 defects have reduced efficiency in repairing DNA adducts and show increased apoptosis in response to platinums conferring sensitivity (Foulkes 2006;Xing et al 2006). The response to taxanes, in BRCA1 deficient cells is reduced apoptosis conferring resistance (Lafarge et al 2001).…”