were identified in 1994 and 1995, the influence of germline BRCA1
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 [19
]). 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
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
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
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
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 [22
], 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
mutations undergoing BCT [7
]. 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
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
germline mutations have a risk for ipsilateral recurrence that is similar to that of other young women. Studies based on series of prevalent cases [8
] 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
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
carriers occurred at a mean time interval of 9.6 years following the initial diagnosis.
Women with BRCA1
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 [30
], 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
-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
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 [32
Nonsurgical options for breast cancer risk reduction in women with BRCA1
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
]. 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
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
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
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
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.