In summary, BRCA1-associated tumors appear to have a prognosis similar to sporadic tumors despite having clinical, histopathologic, and molecular features, which indicate a more aggressive phenotype. BRCA1 mutation carriers who do not receive chemotherapy may have a worse prognosis. However, because most BRCA1-associated breast cancers are triple negative, they are usually treated with adjuvant chemotherapy. Work is ongoing to determine whether BRCA1-associated breast cancers should receive different therapy than sporadic tumors. (Refer to the Role of BRCA1 and BRCA2 in response to systemic therapy section of this summary for more information.)
BRCA2-related breast cancer
Early studies of the prognosis of BRCA2 associated breast cancer have not shown substantial differences in comparison with sporadic breast cancer.[232,234,235,236] A small study reported statistically significant higher OS in BRCA2 mutation carriers with metastatic breast cancer.
Role of BRCA1 and BRCA2 in response to systemic therapy
A growing body of preclinical and clinical literature suggests a differential response of BRCA-related breast cancers to systemic chemotherapy. This is based on the emerging understanding of the functions of these genes in response to DNA damage and mitotic spindle machinery control. As several chemotherapeutic agents target either DNA or mitotic spindle structural integrity, the lack of BRCA functions could alter response to these agents. Intact BRCA1 and BRCA2 are important in DNA repair by homologous recombination. Preclinical studies of BRCA1 and BRCA2 deficient cell lines have suggested increased sensitivity to drugs which cause DNA damage that is repaired by homologous recombination, such as cisplatin, carboplatin and mitomycin C.[237,238] Conversely, intact BRCA1 may be important for spindle poisons, such as taxanes, to be effective.[239,240] Preclinical models suggest decreased sensitivity to these drugs in mutated cell lines.[241,242]
Evidence of the role of BRCA1/BRCA2 mutations in humans is preliminary. A number of small studies have suggested increased clinical response rates, particularly in BRCA1 mutation carriers, but design limitations make it difficult to use these studies to guide clinical recommendations. A small study reported statistically significant higher sensitivity to first-line treatment in BRCA2 mutation carriers with metastatic breast cancer compared with those with sporadic metastatic cancer; conversely, no statistically significant differences were observed for BRCA1 carriers with metastatic breast cancer.
Retrospective and prospective studies [243,244,245,246] have suggested a higher-than-expected response rate to chemotherapy in BRCA1 mutation carriers receiving neoadjuvant chemotherapy for breast cancer, especially when using cisplatin. Several studies have been published regarding the Polish experience on the use of preoperative chemotherapy in BRCA1 mutation carriers. The largest report  includes data on 102 BRCA1 mutation carriers of which 51 were described in two prior studies.[247,243] Women were identified from a registry of 6,903 patients. Those with a Polish founder mutation in BRCA1 (5382insC, C61G, or 4153delA) who had also received preoperative chemotherapy were included. Of these 102 women, 22% had a pathologic complete response (pCR). Twelve women received cisplatin chemotherapy as part of a clinical trial of whom 10 had a pCR (83%). All other patients were examined retrospectively. Of these, 14 received cyclophosphamide, methotrexate, and fluorouracil with one pCR (7%), 25 received doxorubicin and docetaxel with two pCR (8%), and 51 received doxorubicin and cyclophosphamide with 11 pCR (22%). To place this in the context of other available data, several retrospective studies in BRCA1 and BRCA2 mutation carriers with largely anthracycline-based chemotherapy have demonstrated clinical complete response rates of 46% to 90% after preoperative chemotherapy.[244,246] A trial of preoperative cisplatin in triple-negative breast cancer patients demonstrated a pCR of 22%; however, both BRCA1 mutation carriers in the study had a pCR.