The overall results demonstrated a significantly increased risk of local failure in BRCA1/2 mutation carriers treated with BCT compared to carriers treated with M; however, breast cancer-specific and overall survival were comparable. The significant differences in rates of local failure by local therapy sharply contrast with the similar rates reported in multiple randomized trials comparing BCT with M [3
]. Given the low prevalence of BRCA1/2-associated breast cancer and the older median age of women in the randomized trials, these studies included predominantly women with sporadic rather than hereditary breast cancer.
As shown by others, the different location and histology in the majority of IBTR's compared to the original cancers and the increased median time to recurrence relative to sporadic breast cancers observed in the present study, is suggestive of the development of new breast cancers rather than true recurrences [12
]. Of note, in patients treated with M, our results demonstrated a prolonged median time of 9.4 years to local failure considerably longer than the average of 2–3 years reported in most surgical series [13
], also suggestive of the development of new cancers. Future studies using genetic profiling of the primary and secondary lesion are needed to definitively categorize these events.
Predictors of local failure varied between BCT and M. Chemotherapy was the only independent predictor in those treated with BCT, and the reduction was consistent with that observed in many BCT studies of sporadic breast cancer [14
]. In fact, rates of local control at 10 and 15 years in carriers treated with BCT and chemotherapy were not significantly different from rates following mastectomy although a trend in second events was observed. These results may suggest an increased chemosensitivity in BRCA1/2-associated breast cancers as recently suggested by Fourquet and colleagues [16
] and should be followed over time. Given the increasing usage of chemotherapy for invasive breast cancer, this reduction in breast events is potentially highly relevant for current practice. Our results also suggested a benefit in local control in BRCA2 carriers treated with hormonal therapy, consistent with other studies [17
Oophorectomy was not found to significantly impact rates of local failure in analyses among all patients treated with BCT or in subset analyses of those with positive estrogen or progesterone receptors or by mutation type. While the exact reason for this is uncertain, it is important to note that 73% of these women received chemotherapy, 30% received hormonal therapy and approximately 80% were premenopausal at diagnosis. Only 16% patients received no adjuvant therapy. Chemotherapy induces menopause in the majority of women over age 40 [19
]. Thus, the lack of a discernable effect of oophorectomy in this study may reflect the fact that many of the patients were likely rendered post-menopausal with adjuvant therapy.
Earlier reports have shown variable rates of IBTR in BRCA1/2 mutation carriers compared to age-matched women with sporadic breast cancer treated with BCT [20
]. In a previous paper by Pierce et al of 160 early stage BRCA1/2 carriers matched to 445 women with sporadic disease, rates of IBTR in the carriers at 10 and 15 years were 12% and 24% compared to 9% and 17% for controls (p=.19) [20
]. The outcomes that differ between the previously published report and the current analysis are primarily the comparison groups and the rate of recurrence in these groups; the rates of IBTR are comparable between the two studies. There is some overlap of carriers between the previously published report and the current analysis; however, patient data has been updated and the overall BCT data set has expanded. Despite this, the rates of IBTR in the two papers are remarkably similar, with 10- and 15-year estimates in the current series of 10.5% and 23.5%.
Despite increased rates of local failure following BCT compared with M in the present report, no differences were observed in rates of distant failure or disease-specific or overall survival between the two cohorts. This is contradictory to recent prospective studies which strongly support a causal relationship between increased rates of local failure and subsequent distant spread [10
]. While our findings may be a result of the limited sample size of the two cohorts, they may also be the result biologic differences of BRCA1/2 associated breast cancer. Local failure in women with sporadic breast cancer may generally represent a true local recurrence and a biologically more aggressive phenotype rather than the second primary cancers suggested in the current report. As mentioned above, BRCA1/2 related breast tumor may have enhanced sensitivity to chemotherapy 16. Furthermore, close follow-up of BRCA1/2 mutation carriers may have led to early detection and treatment of new cancers thus minimizing the opportunity for distant spread. Our results will need to be followed over time and validated in prospective studies, but at present, our data at 10 and 15 years do not suggest an adverse effect of a local recurrence/new primary upon systemic failure.
We acknowledge the limitations of the current study. Although the study consists of patients followed prospectively in high risk clinics, it is a predominantly prevalent rather than incident cohort which results in survivorship and ascertainment biases. Patients attended high risk clinics or were enrolled in kConFab sometimes many years after their first breast cancer diagnosis, so patients who died early from their breast cancer are less likely to be included in this study. Therefore, our estimates for overall and breast-cancer specific survival may be higher than for a population-based incident cohort of mutation carriers. Similarly, those with more than one breast cancer diagnosis may have been more likely to have been ascertained by kConFab and the high risk clinics. Thus, the frequency of second breast cancer events and CBC seen in this study may also overestimate the true rate that would be seen in a population-based incident cohort. Likewise, biases may be hidden within treatment choice (BCT versus M) that cannot be fully adjusted for by the available patient and tumor characteristics. However, it should be noted that patient data in both cohorts was acquired in the same manner, and that all data submitted from the collaborating institutions of patients who met the study criteria were included in the analysis. Ideally, these patient groups should be randomized to treatment (BCT versus M). However, given that the surgical decision-making process is highly personal and based upon complicated therapeutic concerns, it is doubtful whether such a study could be ethically performed.
In conclusion, our results demonstrate a significantly greater risk of local recurrence but no difference in distant failure or disease-specific or overall survival for patients with a deleterious BRCA1/2 mutation treated with BCT when compared to those treated with M. Within the BCT-treated group, use of adjuvant chemotherapy was significantly associated with reduced rates of IBTR. Among women who received adjuvant chemotherapy and BCT, local control did not significantly vary compared to control rates in women treated with mastectomy. These findings should be considered when patients with BRCA1/2-associated breast cancer are considering their local treatment options and for patients considering BCT, discussion of the role of chemotherapy not only for systemic control but also local control would be relevant. CBC was common in all patient subgroups whether treated with BCT or M. Thus, preventive strategies for the contralateral breast require strong consideration upon diagnosis of a BRCA1/2-associated breast cancer.