The major breast cancer predisposing genes BRCA1 and BRCA2 were identified in 1994 and 1995, respectively 12. Unfortunately, the optimal clinical approach to women who develop hereditary breast cancer remains incompletely defined. Studies of the outcomes of women with BRCA1/BRCA2-related cancer have yielded conflicting results. Several reports suggested that women with germline mutations in BRCA1 are more likely to die from their disease than are women with sporadic breast cancer 3456. However, other studies did not confirm these observations 78. Fewer studies have focused on BRCA2-related breast cancer 910.

Certain unique barriers have impeded the analysis of germline BRCA1/BRCA2 status as a prognostic factor. Because informed consent is required for genetic testing, and individuals may decline such testing for a variety of reasons, it has been difficult to develop prospective cohorts for outcome studies. On the other hand, testing generally requires the provision of a blood sample, which may introduce a survival bias in the conduct of retrospective studies. Both of these potential selection biases may be avoided through the use of a retrospective design in which BRCA1/BRCA2 mutations are sought in archival tissue from women who have undergone treatment for cancer, and in whom the clinical outcomes are known. Genetic testing is performed on anonymized tissue specimens, and comparisons are made between the women who do and those who do not have mutations. This design presupposes that the BRCA1/BRCA2 mutation spectrum in the study group is limited and predefined. This is the case for women of Ashkenazi Jewish descent, because two specific mutations of BRCA1 (185delAG and 5382insC) and one mutation of BRCA2 (6174delT) constitute the great majority of mutations identified in this population, and these are easily detectable in paraffin-embedded material 11121314. The present study employed this retrospective, anonymized design to examine the outcomes of Ashkenazi women with invasive breast cancer undergoing breast-conserving therapy (BCT) at two institutions in the USA and Canada.

Although BRCA1 and BRCA2 were identified in 1994 and 1995, the influence of germline BRCA1/BRCA2 mutations on the outcome of women with breast cancer has remained undefined. Several retrospective studies of affected mutation carriers identified by familial cancer risk clinics failed to demonstrate any differences in survival when women with mutations were compared with various control groups (for reviews 1920). However, because only women who survived their breast cancer were able to undergo genetic testing and be identified as mutation carriers in these prevalent series, a survival bias may have prevented the detection of a negative impact of BRCA1/BRCA2 mutations on outcome. The anonymized design of the current retrospective study circumvented this potential bias by ensuring that all patients within the study group were genotyped, without regard for vital status.

In the present study, women undergoing BCT for early stage invasive breast cancer demonstrated significantly shorter breast cancer specific and overall survival if they carried a germline BRCA1 mutation but not a BRCA2 mutation. This suggests that the clinical outcome of women with germline mutations may vary depending on which gene is mutated, and even possibly on the position of the mutation within a particular gene. However, the present study, examining the consequences of an intentionally restricted set of mutations in a limited sample, cannot definitively resolve this question. Larger studies, preferably of prospectively ascertained incident cohorts, are necessary.

The adverse prognosis conferred by a BRCA1 mutation was not attributable to differences in tumor size or axillary nodal status, which indicates that the impact of germline status on clinical outcome is not the result of an association with advanced stage at diagnosis. Several studies have demonstrated that breast cancers arising in women with BRCA1/BRCA2 mutations, particularly those in BRCA1, frequently manifest adverse pathologic and biologic features, such as high histologic grade, hormone receptor negativity, p53 mutation, aneuploidy, and high S-phase fraction 19. Studies conducted in sporadic breast cancer have previously demonstrated the negative prognostic significance of each of these factors. Whether the prognostic significance of BRCA1/BRCA2 status is completely independent of all of these other parameters cannot be resolved by the present study. BRCA1-related breast cancers in this series, as in others, were significantly more likely to be estrogen receptor negative than were cancers not associated with BRCA1 mutations, and estrogen receptor status was associated with breast cancer mortality in univariate analysis. However, germline status remained a significant prognostic indicator in the multivariate model, indicating that the adverse effect of mutation status on outcome is independent of the association with estrogen receptor negative phenotype. The robustness of this observation is limited to some degree by the fact that receptor status was unknown for a significant proportion of patients, in part because some of these cases were diagnosed before routine receptor testing and in part because the small size of some tumors prevented receptor determination using the dextran-coated charcoal method in use at the time.

The design of the present study precluded a separate analysis of the role of grade in determining outcome in BRCA1 carriers. However, it is known that the majority of BRCA1-related breast cancers are high grade, infiltrating ductal breast cancers 21. It would not significantly change the conclusions of this study if it could be demonstrated that the independent negative impact observed is attributable to the 'downstream' phenotypic consequences of the presence of a BRCA1 mutation.

Some preclinical studies have demonstrated that mouse embryonic cells lacking functional Brca1 protein are sensitive to specific chemotherapeutic agents such as cisplatinum and mitomycin C 2223, and similar results have been seen in human breast cancer cells null for BRCA1 protein 24. These observations have raised the possibility that human BRCA1-associated breast cancers might also be differentially sensitive to chemotherapy. The current analysis is consistent with this hypothesis, because the negative prognostic influence of a germline BRCA1 mutation appeared to be reduced in women receiving adjuvant chemotherapy, and, in fact, lost independent statistical significance in this group. Furthermore, standard chemotherapy regimens do not include mitomycin-C or cisplatinum, and it remains possible that BRCA1-associated breast cancers may be even more sensitive to these agents. However, the design of the present study is such that these observations must be considered hypothesis generating. Further exploration should take place within the context of prospective trials.

In the present study, women with germline mutations experienced a risk for metachronous ipsilateral breast cancer that was not significantly different from that in women without mutations. Several studies have described the incidence of subsequent ipsilateral disease in women with BRCA1/BRCA2 mutations undergoing BCT 78152526. In these series, ipsilateral tumor recurrence rates ranged from 1% to 20% at 5 years, which are in the range previously reported in series of young women undergoing BCT. A recent analysis of mutation carriers who had survived a mean of 14 years after their breast cancer diagnosis 27 indicated a 49% estimated risk for ipsilateral cancer after 10 years of follow up. However, studies such as this, which analyze prevalent groups of long-term survivors, may overestimate the risk that a newly diagnosed woman with a BRCA1/BRCA2 mutation will suffer an ipsilateral breast cancer, because a significant fraction of newly diagnosed women will unfortunately die from their breast cancer and thus will not have lived long enough to develop a second ipsilateral tumor. Thus, ipsilateral cancer estimates derived from such studies may be misleading for newly diagnosed women attempting to make the difficult choice between breast conservation and bilateral mastectomy.

Taken together, the results of the available series suggest, at least up to 10 years of follow up, that women with BRCA1/BRCA2 germline mutations have a risk for ipsilateral recurrence that is similar to that of other young women. Studies based on series of prevalent cases 82627 suggest, however, that women who are long-term survivors may have an increased risk of new second primary malignancies within the treated breast. This interpretation is supported by a further analysis of cases reported by Haffty and colleagues 28, in which all eight patients with deleterious BRCA1/BRCA2 mutations had new primary ipsilateral breast cancer, whereas patients without deleterious mutations had both true recurrences and new primary breast cancers (P = 0.06). The cancers occurring in BRCA1/BRCA2 carriers occurred at a mean time interval of 9.6 years following the initial diagnosis.

Women with BRCA1/BRCA2 mutations are at substantial increased risk for metachronous contralateral breast cancer throughout the follow-up period. Although this increased contralateral risk could reflect an increased sensitivity to radiation-induced malignancies initiated by scatter from adjuvant radiotherapy, the contralateral incidence rate is similar to that observed in affected mutation carriers after mastectomy 29 and in prospectively followed cohorts of heterozygotes 3031, which suggests that the observed contralateral breast cancers are most likely the direct result of the underlying genetic predisposition. The apparent paradox of differential ipsilateral and contralateral risk, as well as differences in estimates of ipsilateral risk according to duration of follow up, may be explained by a model that proposes that women presenting with BRCA1/BRCA2-associated breast cancer have multiple foci within both breasts at various stages of evolution toward malignancy. These foci may be eliminated or substantially retarded by adjuvant radiotherapy of the initially affected breast, preventing or delaying their appearance as metachronous ipsilateral cancers. In the untreated contralateral breast, however, occult lesions existing at the time of initial diagnosis could proceed unimpeded in their progression to malignancy, resulting in an unaltered risk for contralateral cancer. Extending the hypothesis, the continued presence of the genetic predisposition may permit the process of carcinogenesis in the affected breast to begin anew once the radiation treatment was completed, and, after a delay, metachronous breast cancers would begin to appear in the treated and untreated breasts at similar rates. This hypothetical model could be tested by careful pathologic examination of breasts of women with BRCA1/BRCA2 mutations undergoing either therapeutic or prophylactic mastectomy to assess the prevalence of occult premalignant and malignant lesions. The results of early reports are conflicting, but there is some evidence for an excess of premalignant changes, particularly for BRCA2 mutation carriers 323334.

Nonsurgical options for breast cancer risk reduction in women with BRCA1/BRCA2 mutations are limited. A previous case–control study 35 suggested that tamoxifen reduced the risk for contralateral cancer by nearly 50% in mutation carriers, but this benefit was not observed in a prospective trial of primary prevention among unaffected women with BRCA1 mutations 36. In the present study, a trend toward a reduction in contralateral breast cancer was seen in mutation carriers who received the drug, although this did not achieve statistical significance. Because the number of women with mutations who received tamoxifen was small, the present series cannot satisfactorily address whether the benefit of tamoxifen in reducing contralateral risk varies between women with BRCA1 and those with BRCA2 mutations. It is of interest that the degree of contralateral risk reduction experienced by the mutation carriers taking tamoxifen in the study was similar to that reported in the previous case–control study, and there was no clear difference between the effects observed in BRCA1 and BRCA2 mutation carriers, but further studies of larger numbers of women are needed before these data can be used to guide clinical practice.

Retrospective anonymized studies such as the one reported here may be more easily performed in populations with a high prevalence of specific founder BRCA1/BRCA2 mutations, such as the Ashkenazim. Non-founder mutations are not identified with this design, and a small number of individuals will thus be misclassified as 'mutation negative' when, in fact, they carry a unique deleterious alteration. However, the number of such cases is likely to be small. In a recent report of 322 Ashkenazi individuals who underwent full sequence analysis of BRCA1 and BRCA2 after negative founder mutation testing, only six (1.9%) were found to carry a unique mutation 37. Because women undergoing complete sequencing were probably encouraged to do so because of a family history of breast or ovarian cancer, the prevalence of unique mutations is likely to be even lower in an unselected population of breast cancer patients such as those reported in the present study. Thus, false-negative classification is unlikely to have significantly affected the results of this study. Nonetheless, the results of the study may not be applicable to all women with BRCA1/BRCA2 mutations. The majority of mutation carriers in the study carried either BRCA1 185delAG (32 out of 42 [76%] of all BRCA1 mutation carriers) or BRCA2 6174delT. It is possible that other mutant alleles may confer different risks for recurrence.

This combined study demonstrates that women with specific BRCA1/BRCA2 mutations who develop breast cancer are at increased risk for death from their disease, particularly if the mutation is in BRCA1. For up to 10 years after diagnosis, the risk for metachronous ipsilateral cancer is similar to that in women without mutations, but the risk for contralateral disease is substantially higher. Taken together, these findings suggest that the possibility of BRCA1/BRCA2-associated breast cancer should be taken into account with other factors when making decisions regarding radiotherapy and adjuvant chemotherapy, but should not be used as a sole factor to determine the appropriateness of BCT. Adjuvant tamoxifen should be given when appropriate to BRCA1/BRCA2 mutation carriers with hormone receptor positive breast cancer, but despite promising data, the true effectiveness of this agent in reducing contralateral breast cancer risk in this group of women remains uncertain.

None declared

BCT = breast-conserving therapy; CI = confidence intervals; HR = hazard ratio; MSKCC = Memorial Sloan-Kettering Cancer Center; PCR = polymerase chain reaction; SMBD-JGH = Sir Mortimer B. Davis-Jewish General Hospital.