Cortesi et al. BMC Cancer 2010, 10:90 http://www.biomedcentral.com/1471-2407/10/90 not surprising that a difference in OS was found and could be explained by the use of alkylating agents, such as platinum-derived drugs, in metastatic disease that are well known to be more effective in BRCA-related tumours [15]. Furthermore, since BRCA1 patients main- tain a statistically significant OS advantage, even after matching each case to four controls for age and tumour grade and disease stage, this result is very important in terms of its practical value, because all confounders have been removed. Robson et al [12] suggested that a BRCA1 mutation was an independent predictor of breast cancer mortality in a multivariate analysis of a group of women who did not receive chemotherapy, but not in women who received adjuvant chemotherapy. In a multivariate analysis, we found that chemotherapy is a prognostic factor for better survival in all patients combined; furthermore, we found that a BRCA1-positive status was an independent predictor for a better survival in all patients and also in the subgroup of patients who received chemotherapy, but not in patients who did not receive chemotherapy. No differences are shown for BRCA1 patients, independently of chemotherapy or not. Also, this result might be explained by the fact that deaths in the treated group of patients were all related to a second tumour, while in the non treated group one of three deaths was caused by breast cancer. In conclu- sion, chemotherapy has a greater protective effect in BRCA1 mutation carriers compared with patients who are BRCA-negative and those with sporadic breast can- cer. Furthermore, since BRCA1-related tumours are more likely to be triple negative, the greatest advantage was shown for ER-negative breast cancer, were che- motherapy is the most active. Hence, increasing the number of BRCA1 carriers identified by correctly select- ing patients with a high probability of having hereditary breast cancer through a 10-year survival analysis could improve the benefit derived from specific chemotherapy agents (i.e., alkylating or PARP-inhibitors). In fact, the chemotherapy benefit is well known because normal BRCA1 and BRCA2 proteins participate with RAD51 in the repair of double-stranded DNA breaks induced by DNA-damaging agents [16-19]. The better prognosis could be due to the deficiency of the BRCA proteins, which confer substantial cellular sensi- tivity to the inhibition of poly (ADP-Ribose) polymerase enzyme (PARP). This polymerase is a key enzyme in the repair of single-stranded DNA damage via the base exci- sion repair pathway. The loss of PARP activity in BRCA mutant cells might lead to the persistence of DNA lesions normally repaired by homologous recombination, resulting in increased chromosome instability and pro- grammed cell death specifically in tumour cells [20,21]. Therefore, because there is no functional protein within Page 8 of 9 the tumour cells, they lose their capacity to repair DNA damage. This might be specifically pronounced for drugs, such as cisplatin, acting through the induction of DNA damage leading to cell death and to a better thera- peutic response. In a small clinical study, Chappuis et al [22] found a benefit in Ashkenazi Jews with locally advanced breast cancer who were BRCA-positive and treated with anthracycline-based chemotherapy regi- mens. In this study, all patients received anthracycline- based neoadjuvant chemotherapy, and 10 of 11 patients with BRCA mutations had a clinical complete response compared with only 8 of 27 BRCA-negative patients with sporadic breast tumours. From this study, it was inferred that tumours with BRCA1 mutations are highly sensitive to anthracycline-based chemotherapy regimens. In our study, patients were considered part of a hospi- tal-based population and were not selected for age, tumour stage, or treatment, which could influence survi- val rates. We were successful in obtaining blood samples from all patients and were able to genotype all the sam- ples we received. The patients were followed for a med- ian of 72 months. Treatment regimens were chosen on the basis of disease staging. The Modena Cancer Registry captures outcome data from almost all patients with can- cer who are treated in the province. Data on pathological diagnosis are verified by a pathologist, and incomplete information is retrieved from medical records when pos- sible. All patients were Caucasian, and it is possible that the chemotherapy sensitivity can be associated with spe- cific modifier genes not found in other populations. Our study has a number of limitations. Tumour stage and hormone receptor status were not routinely recorded, particularly during the first period. Since we tested only a subpopulation of patients with a positive family history of breast cancer, it is possible that some hereditary cases were misclassified; but we found that only 1% of mutations occurred in the IS increased risk group suggesting that the number of BRCA1 carriers in the sporadic group would be very low. Since we identi- fied only 80 mutation carriers, the subgroup analysis relied on a small number of subjects. In conclusion, our study is the first to evaluate a rela- tionship between familial risk of breast cancer and a genetic assessment in terms of DFS and OS. We pro- pose that the increased survival associated with a family history of breast cancer, suggesting hereditary breast cancer according to the Modena criteria, should be con- sidered with respect to BRCA1 analysis as a predictor of mutations. We feel that randomized studies need to be designed to further address the relationship between BRCA1 mutations and sensitivity to chemotherapy, and further clinical investigations are required to determine whether the BRCA1 status can be used to predict treat- ment outcomes.